Zakażenie wirusem brodawczaka ludzkiego (hpv)

Zakażenie wirusem brodawczaka ludzkiego (hpv)
Patofizjologia i mechanizm

Wirus brodawczaka ludzkiego (HPV) to mały, bezotoczkowy wirus DNA z rodziny Papillomaviridae, infekujący komórki nabłonkowe skóry i błon śluzowych, szczególnie warstwę podstawną nabłonka wielowarstwowego płaskiego. Zidentyfikowano ponad 200 typów HPV, z których około 40 przenoszonych jest drogą płciową. Typy wysokiego ryzyka (HR-HPV), takie jak HPV 16 i 18, są odpowiedzialne za 99% przypadków przedrakowych zmian szyjki macicy oraz około 66% raków szyjki macicy globalnie. Mechanizm infekcji obejmuje początkowe wiązanie z proteoglikanami siarczanu heparanu (HSPG) na błonie podstawnej po urazie nabłonka, a następnie endocytozę i transport do jądra komórkowego, gdzie wirus replikuje swój genom. Białka wirusowe E6 i E7, kluczowe onkoproteiny HR-HPV, inaktywują supresory nowotworowe p53 i pRb, prowadząc do niekontrolowanej proliferacji komórek, niestabilności genomowej i transformacji nowotworowej. Integracja genomu HPV do DNA gospodarza, szczególnie utrata funkcji białka E2, jest krytycznym etapem w karcynogenezie szyjki macicy.

Wstęp do zakażenia wirusem brodawczaka ludzkiego (HPV)

Wirus brodawczaka ludzkiego (Human Papillomavirus, HPV) jest małym, bezotoczkowym wirusem DNA o ikozaedrycznej symetrii, posiadającym dwuniciowe kolistą cząsteczkę DNA o długości około 8000 par zasad. Należy on do rodziny Papillomaviridae i charakteryzuje się zdolnością do infekowania komórek nabłonkowych skóry i błon śluzowych. Zidentyfikowano ponad 200 różnych typów HPV, z których ponad 40 jest przenoszonych drogą kontaktów seksualnych. Wirusy HPV wykazują znaczną specyficzność w stosunku do tkanek nabłonkowych i ewoluowały w taki sposób, aby ograniczyć infekcję do komórek warstwy podstawnej nabłonka wielowarstwowego płaskiego, który jest jedyną tkanką, w której się replikują.¹²³

Na podstawie związku z transformacją nowotworową, HPV dzieli się na typy wysokiego ryzyka onkogennego (HR-HPV) oraz niskiego ryzyka (LR-HPV). Typy wysokiego ryzyka (w tym HPV 16, 18 i inne) mogą powodować zmiany dysplastyczne niskiego i wysokiego stopnia, które są prekursorami raka, oraz raki narządów płciowych. HPV wysokiego ryzyka wykrywa się w 99% przypadków przedrakowych zmian szyjki macicy. Typ 16 jest przyczyną około 50% raków szyjki macicy na świecie, a typy 16 i 18 razem odpowiadają za około 66% przypadków raka szyjki macicy. Dodatkowe pięć typów wysokiego ryzyka (31, 33, 45, 52 i 58) odpowiada za kolejne 15% przypadków raka szyjki macicy i 11% wszystkich nowotworów związanych z HPV.⁴⁵⁶

Mechanizm zakażenia wirusem HPV

Mechanizm infekcji wirusami HPV jest wyjątkowy i w niektórych aspektach niezwykły. Wiele jego cech jest adaptacją do stylu życia wirusa, takiego jak ograniczenie cyklu życiowego do terminalnie różnicującego się nabłonka wielowarstwowego płaskiego i zdolność do opóźniania indukcji skutecznej odpowiedzi immunologicznej przez dłuższy czas.⁷⁸

Inicjacja zakażenia

Niedawne badania na modelu szyjkowo-pochwowym myszy wykazały, że wirus początkowo nie może wiązać się z keratynocytami in vivo. Zamiast tego musi najpierw związać się za pośrednictwem głównego białka kapsydu L1 z proteoglikanami siarczanu heparanu (HSPG) na segmentach błony podstawnej (BM) odsłoniętych po urazie nabłonka i przejść zmianę konformacyjną, która eksponuje N-koniec białka kapsydu L2 na działanie furyny.⁹¹⁰

Proteoliza L2 odsłania wcześniej niewidoczną powierzchnię L1, która wiąże się z jeszcze nieokreślonym receptorem powierzchniowym na keratynocytach, które migrowały nad BM, aby zamknąć ranę. Papillomawirusy są jedynymi znanymi wirusami, które inicjują swój proces infekcyjny w miejscu pozakomórkowym.¹¹¹²

Do zakażenia dochodzi poprzez mikrourazy nabłonka, które umożliwiają wirusowi dostęp do komórek warstwy podstawnej. Receptor dla wniknięcia wirusa do komórki nie jest jeszcze w pełni poznany, chociaż siarczan heparanu pośredniczy w początkowym przyłączeniu wirionów do komórek. Wiązanie HPV wywołuje zmiany konformacyjne w kapsydzie, które wpływają zarówno na białka L1, jak i L2, a takie zmiany są warunkiem wstępnym do interakcji z receptorem pochłaniania.¹³¹⁴

Wnikanie do komórki

Po początkowym związaniu z HSPG i cięciu przez furynę, wirus jest przenoszony do niezidentyfikowanego receptora na powierzchni komórki. Następnie wnika do komórki za pośrednictwem szlaku endocytarnego i w ciągu 4 godzin lokalizuje się we wczesnym endosomie. W ciągu 12 godzin wirus traci osłonkę w późnym endosomie, a kompleks genomu wirusowego z białkiem L2 zostaje uwolniony.¹⁵¹⁶

Większość typów HPV, które były badane, wydaje się wchodzić do komórki za pośrednictwem mechanizmu endocytozy zależnej od klatryny, chociaż wiele danych jest niejednoznacznych i niespójnych. Niektóre typy HPV mogą wykorzystywać alternatywne szlaki, aby wniknąć do komórek, takie jak droga zależna od kaweoli lub wykorzystanie domen wzbogaconych w tetraspaniny jako platformy dla wchłaniania wirusa.¹⁷

Po ucieczce z endosomu, zarówno los L1, jak i mechanizm, przez który kompleks L2-genom przemieszcza się przez cytoplazmę i do jądra, są słabo poznane. Po dostaniu się do jądra kompleks L2-genom lokalizuje się w specyficznych domenach jądrowych zwanych ciałami ND10, gdzie rozpoczyna się transkrypcja genomu wirusowego. Lokalizacja w ND10 promuje transkrypcję genomu wirusowego.¹⁸¹⁹

Proces infekcyjny jest niezwykle powolny i asynchroniczny zarówno in vivo, jak i w hodowlach komórkowych, a inicjacja transkrypcji zajmuje od 12 do 24 godzin. Przedłużona ekspozycja determinant neutralizujących przeciwciała, gdy wiriony znajdują się na BM i powierzchni komórki, może częściowo tłumaczyć niezwykłą skuteczność szczepionek opartych na przeciwciałach neutralizujących skierowanych przeciwko cząstkom wirusopodobnym L1 lub domenie L2 eksponowanej po cięciu przez furynę.²⁰²¹

Cykl życiowy HPV i integracja z komórką gospodarza

Cykl życiowy HPV jest ściśle związany z programem różnicowania zainfekowanej komórki gospodarza – keratynocyta, przy czym produkcja dojrzałych cząstek wirusa jest ograniczona do zróżnicowanych komórek warstwy przypodstawnej.²²²³

Replikacja i utrzymanie genomu wirusowego

Po infekcji komórek warstwy podstawnej przez HPV dochodzi do aktywacji kaskady ekspresji genów wirusowych, co prowadzi do produkcji około 20-100 pozachromosomalnych kopii DNA wirusowego na komórkę. Ta średnia liczba kopii jest stabilnie utrzymywana w niezróżnicowanych komórkach warstwy podstawnej przez cały czas trwania infekcji.²⁴

Jednymi z pierwszych białek wirusowych, które ulegają ekspresji, są czynniki replikacyjne E1 i E2. Białka te tworzą kompleks, który wiąże się z sekwencjami w wirusowym miejscu inicjacji replikacji i działa w celu rekrutacji komórkowych polimeraz i białek dodatkowych do pośredniczenia w replikacji. Białko E1 wykazuje również aktywność helikazy, umożliwiając rozdzielenie nici DNA wirusa przed kompleksem replikacyjnym. E2 jest białkiem wiążącym DNA w sposób specyficzny dla sekwencji, które pomaga rekrutować E1 do miejsca inicjacji, ale odgrywa również rolę w regulacji transkrypcji wirusowej z wczesnego promotora.²⁵²⁶

Do aktywacji replikacji DNA papillomawirusa niezbędne są zarówno białka E1, jak i E2. Początkowo E1 jako dimer i E2 jako dimer wiążą się z wirusowym miejscem inicjacji, co prowadzi do utworzenia trzeciorzędowego kompleksu E1-E2, który hamuje niespecyficzne wiązanie E1-DNA.²⁷

Różnicowanie i amplifikacja wirusa

Gdy zainfekowane komórki podstawne dzielą się, genomy wirusowe są rozdzielane do komórek potomnych, z których jedna odłącza się od warstwy podstawnej, migruje w kierunku warstwy ziarnistej i ulega różnicowaniu. W normalnym niezainfekowanym nabłonku komórki opuszczają cykl komórkowy, gdy opuszczają warstwę podstawną, co często prowadzi do utraty jąder w komórkach warstwy przypodstawnej.²⁸

Gdy zainfekowane komórki opuszczają warstwę podstawną, pozostają aktywne w cyklu komórkowym dzięki działaniu białka E7. Komórki ponownie wchodzą w fazę S w silnie zróżnicowanych komórkach i aktywują ekspresję komórkowych czynników replikacyjnych wymaganych do replikacji wirusowej. Obecność E7 prowadzi do charakterystycznego zatrzymania jąder we wszystkich warstwach zainfekowanego nabłonka.²⁹

Najbardziej prawdopodobny mechanizm amplifikacji wirusowego DNA koncentruje się na aktywacji ekspresji późnego promotora wirusowego, co prowadzi do wysokiego poziomu ekspresji transkryptów kodujących wirusowe białka replikacyjne E1 i E2, wraz z późnymi genami. W przeciwieństwie do wczesnego promotora, późny promotor nie jest negatywnie regulowany przez białko E2, a wysokie poziomy ekspresji występują po różnicowaniu, prowadząc do amplifikacji DNA wirusowego. Ten wzrost liczby matryc powoduje dalszy wzrost ekspresji białek replikacyjnych.³⁰

Integracja genomu i potencjał onkogenny

W zakażeniach niskiego stopnia genomy HPV wysokiego ryzyka występują jako episomy, podczas gdy w trakcie progresji do zmian wysokiego stopnia lub raków genom często jest zintegrowany w sekwencje gospodarza. Ta integracja zwykle zachodzi w obrębie otwartej ramki odczytu E2 i prowadzi do utraty represyjnego działania E2, co prowadzi do wyższych poziomów ekspresji E6 i E7.³¹³²

Integracja genomu HPV do genomu komórkowego odgrywa kluczową rolę w rozwoju raka. Białka E6 i E7 działają modyfikując środowisko komórkowe, umożliwiając amplifikację genomu wirusowego w zróżnicowanych komórkach nabłonkowych, które normalnie byłyby niekompetentne do replikacji DNA.³³³⁴

Niedawne badania wskazują na istnienie skomplikowanego interaktomu HPV, czyli sieci interakcji międzycząsteczkowych E6 i E7 z białkami komórki gospodarza. Integracja prowadzi zazwyczaj do zwiększonej ekspresji i stabilności transkryptów kodujących wirusowe onkogeny E6 i E7, które, jak wiadomo, inaktywują i/lub przyspieszają degradację licznych białek komórkowych, w tym białka retinoblastoma (przez E7) i p53 (przez E6).³⁵

Rola białek wirusowych w patogenezie

Wirusy HPV kodują szereg białek, które odgrywają kluczową rolę w cyklu replikacyjnym wirusa i potencjalnie w transformacji nowotworowej. Należą do nich białka wczesne (E1, E2, E4, E5, E6, E7) oraz późne (L1, L2).³⁶³⁷

Białka E6 i E7

Białka E6 i E7 typów HPV wysokiego ryzyka działają jako wirusowe onkoproteiny i są głównymi arbitrami onkogenezy indukowanej przez HPV. Białka te zmieniają kontrolę cyklu komórkowego i odgrywają główną rolę w hamowaniu wrodzonej odpowiedzi immunologicznej gospodarza na HPV.³⁸³⁹

Białko E6 (150-160 aminokwasów, około 18 kDal) jest główną onkoproteiną. Hamuje apoptozę i różnicowanie. Wpływa na kształt komórki, polarność, mobilność i sygnalizację. E6 wiąże się z białkiem supresorowym p53 jako część trimerycznego kompleksu z komórkową ligazą ubikwityny, E6AP, prowadząc do szybkiego obrotu p53. Normalnie p53 działa, aby zapobiec wzrostowi komórek i promuje śmierć komórki w obecności uszkodzenia DNA. p53 reguluje również w górę białko p21, które blokuje formowanie kompleksu cykliny D/Cdk4, tym samym zapobiegając fosforylacji białka retinoblastoma (RB), a w konsekwencji zatrzymuje progresję cyklu komórkowego, zapobiegając aktywacji E2F.⁴⁰⁴¹

E7 wiąże się z białkiem supresorowym guza retinoblastoma pRb oraz z mniejszymi białkami, takimi jak p107 i p130, hamując ich działanie, a w przypadku onkogennych HPV, prowadząc do przyspieszonej degradacji. E7 może również bezpośrednio oddziaływać z E2F1 w sposób niezależny od retinoblastomy, przy czym białko E7 wytwarzane przez HR-HPV wiąże się ściślej z E2F1 niż z LR-HPV i aktywuje transkrypcję zależną od E2F1 i aktywność promotora, które uczestniczą w deregulacji cyklu komórkowego i indukcji transformacji.⁴²⁴³

Białko E5

Białko E5 jest odpowiedzialne za kontrolę wzrostu komórek, różnicowanie i modulację immunologiczną. Onkoproteina HPV E5 jest jednym z możliwych efektorów, które pozwalają wirusowi uciec przed układem odpornościowym gospodarza poprzez obniżenie regulacji powierzchniowego klasycznego głównego układu zgodności tkankowej klasy I (MHC I), a nie nieklasycznego MHC I.⁴⁴⁴⁵

Brak klasycznego MHC I w zainfekowanych komórkach wyrażających E5 pozwoliłby na uniknięcie zabijania przez limfocyty T cytotoksyczne (CTL) i tym samym na ustanowienie i utrzymanie infekcji wirusowej. Obniżenie regulacji MHC klasy I przez onkoproteinę E5 pozwala zainfekowanej komórce uniknąć odpowiedzi immunologicznej zależnej od komórek i potencjalnie umożliwia innym onkoproteiną HPV ustanowienie i utrzymanie infekcji wirusowej.⁴⁶⁴⁷

Białka E1 i E2

Białka E1 i E2 działają jako czynniki rozpoznające pochodzenie, a także regulatory wczesnej transkrypcji wirusowej. Białko E2 jest białkiem wiążącym DNA specyficznie dla sekwencji, które pomaga rekrutować E1 do źródła, ale również odgrywa rolę w regulacji transkrypcji wirusowej z wczesnego promotora.⁴⁸⁴⁹

Niekontrolowana ekspresja onkogenów E6 i E7 jest głównie napędzana przez utratę funkcji regulacyjnej wirusowego białka E2. Onkogenna aktywność HR-HPV jest nie tylko wystarczająca do progresji złośliwości, ale również dla innych kroków generujących guzy wymaganych do wytworzenia raka inwazyjnego, takich jak koinfekcja z innymi wirusami, czynniki stylu życia, takie jak wysoka parzystość, palenie, żucie tytoniu, długotrwałe stosowanie środków antykoncepcyjnych oraz odpowiedzi immunologiczne, takie jak stymulacja przewlekłego zapalenia zrębu i immunologiczne odchylenie w mikrośrodowisku guza.⁵⁰⁵¹

Białka L1 i L2

L1 to główne białko kapsydu, a L2 to mniejsze białko kapsydu, które wraz z L1 pośredniczy w zakaźności HPV. L2 jest białkiem wielofunkcyjnym zlokalizowanym wewnętrznie, z rolami w enkapsydacji genomu, interakcji L1 i stabilizacji kapsydu, ucieczce endosomalnej wirionów i transporcie jądrowym genomu HPV.⁵²⁵³

Obecne szczepionki przeciwko HPV opierają się na cząstkach wirusopodobnych (VLP), które są tworzone przez komponenty powierzchniowe HPV. VLP nie są zakaźne, ponieważ brakuje im DNA wirusa. Jednak ściśle przypominają naturalny wirus, a przeciwciała przeciwko VLP mają również aktywność przeciwko naturalnemu wirusowi. VLP okazały się silnie immunogenne, co oznacza, że indukują wysokie poziomy produkcji przeciwciał przez organizm. To sprawia, że szczepionki są wysoce skuteczne.⁵⁴

Mechanizmy unikania odpowiedzi immunologicznej

HPV ewoluował w kierunku mechanizmów pozwalających na uniknięcie nadzoru immunologicznego gospodarza i opóźnienie rozwiązania infekcji. Charakterystyki cyklu życiowego HPV odgrywają kluczową rolę w unikaniu wykrycia przez układ odpornościowy i patogenności wirusa. Cykl życiowy HPV charakteryzuje się nielityczną odpornością zainfekowanych komórek oraz brakiem wiremii i sygnałów zapalnych.⁵⁵⁵⁶

Mechanizmy unikania nadzoru immunologicznego

Nielityczna cecha HPV jest jednym z wyjaśnień dla uniknięcia rozpoznania infekcji HPV. HPV nie lizuje zainfekowanej komórki ani nie powoduje wiremii, a to zmniejszy ekspozycję antygenu wirusowego na odporność komórkową i w konsekwencji brak stanu zapalnego.⁵⁷

HPV ułatwia ten mechanizm za pomocą wczesnych onkoprotein, E5, E6 i E7, które mają zdolność do ingerowania i aktywnego uczestniczenia w obniżeniu regulacji układu odpornościowego gospodarza. Regulacja w dół MHC klasy I przez onkoproteinę E5 pozwala zainfekowanej komórce uniknąć odpowiedzi immunologicznej zależnej od komórek, co potencjalnie umożliwia innym onkoproteiną HPV ustanowienie i utrzymanie infekcji wirusowej.⁵⁸

Obniżenie regulacji MHC I jest imperatywnym mechanizmem uniknięcia klirensu mediowanego przez CTL, jednak brak powierzchniowego MHC I aktywuje komórki NK do ataku i zniszczenia zainfekowanych komórek. HPV może używać strategii unikania immunologicznego nie tylko poprzez ukrywanie się przed rozpoznaniem przez komórki odpornościowe poprzez obniżenie regulacji antygenów wirusowych, ale także poprzez zakłócanie ekspresji białek odpowiedzi immunologicznej, co dodatkowo sprzyja długotrwałemu utrzymywaniu się infekcji wirusowej.⁵⁹⁶⁰

Rola infekcji przewlekłej w patogenezie

Chociaż częstość infekcji jest wysoka, większość infekcji ustępuje samoistnie w ciągu roku lub dwóch. Niewielka część zainfekowanych osób staje się trwale zainfekowana; przewlekła infekcja jest najważniejszym czynnikiem ryzyka rozwoju raka szyjki macicy. Infekcja HPV wysokiego ryzyka jest uważana za konieczną dla rozwoju raka szyjki macicy, ale sama w sobie nie jest wystarczająca do wywołania raka. Ogromna większość kobiet z infekcją HPV, nawet tych z typami HPV wysokiego ryzyka, nie rozwija raka.⁶¹⁶²

Odpowiedzi immunologiczne gospodarza walczą z infekcją HPV i eliminują większość części wirusowej (prawie 90%) w ciągu 2-3 lat lub pozostają w fazie uśpienia, podczas gdy pozostałe 10% przekształca się w infekcje przewlekłe; jednak tylko 1% może powodować raka szyjki macicy. Przetrwała infekcja HPV i niższa odpowiedź immunologiczna gospodarza wspólnie wspierają wszczynanie karcynogenezy poprzez konwersję zmian śródnabłonkowych niskiego stopnia (LSIL) w zmiany śródnabłonkowe wysokiego stopnia (HSIL), które ostatecznie przekształcają się w inwazyjną postać raka szyjki macicy.⁶³⁶⁴

Zaangażowanie HPV w indukcję i progresję raka może zająć wiele lat, zanim przekształci się w raka z pomocą różnych kroków stymulujących guzy, takich jak białka E6/E7, które oddziałują z białkami komórkowymi. Dodatkowo, kilka raportów sugerowało, że niezrównoważona odporność i przewlekłe zapalenie w mikrośrodowisku guza (TME) mogą wywołać przedrakowe zmiany szyjki macicy, które przekształcają się w raka inwazyjnego.⁶⁵

Patogeneza raka związanego z HPV

Przetrwała infekcja typami HPV wysokiego ryzyka jest wymagana do progresji od normalnego nabłonka szyjki macicy do zmian przednowotworowych, a ostatecznie do inwazyjnego raka szyjki macicy, z wkładem dodatkowych mutacji genetycznych i zewnętrznych kofaktorów przez długie okresy czasu.⁶⁶

Rola białek E6 i E7 w karcynogenezie

Wirusowe onkoproteiny E6 i E7 mogą indukować uszkodzenia DNA, nieprawidłowości centrosomu i defekty segregacji chromosomów, prowadząc do niestabilności chromosomowej. HPV dąży do integracji swojego genomu do jądrowego DNA. Niektóre z wczesnych genów wyrażanych przez HPV, takie jak E6 i E7, działają jako onkogeny, które promują wzrost guza i transformację złośliwą. Integracja genomu HPV może również powodować karcynogenezę przez promowanie niestabilności genomowej związanej ze zmianami w liczbie kopii DNA.⁶⁷⁶⁸⁶⁹

E6 typów HPV wysokiego ryzyka wiąże się z p53 jako część kompleksu z komórkową ligazą ubikwityny E6AP, prowadząc do przyspieszonej degradacji p53 i związanej z tym utraty funkcji regulatora cyklu komórkowego, co umożliwia nieograniczoną proliferację komórek z uszkodzonym DNA. E7 wiąże się z pRb, powodując uwolnienie czynnika transkrypcyjnego E2F, co ułatwia przejście komórki przez punkt kontrolny G1/S i prowadzi do niekontrolowanej proliferacji komórek.⁷⁰⁷¹

E6 ma również zdolność do aktywacji katalitycznej podjednostki telomerazy (hTERT), która dodaje powtórzenia heksamerowe do telomerowych końców chromosomów. Aktywność telomerazy jest normalnie ograniczona do przedziału proliferacyjnego nabłonka, a aktywacja jest związana z nieśmiertelnością komórek i karcynogenezą.⁷²⁷³

Integracja genomu i transformacja nowotworowa

Integracja genomu HPV do genomu komórki gospodarza jest kluczowym wydarzeniem w karcynogenezie mediowanej przez HPV, prowadzącym do aberracyjnej proliferacji i progresji złośliwej. Karcynogeneza szyjki macicy jest procesem wieloetapowym związanym z akumulacją zmian DNA w genach komórki gospodarza. Te zmiany obejmują zarówno zmiany epigenetyczne, jak i genetyczne w onkogenach i genach supresorowych guza, które są kluczowymi regulatorami progresji cyklu komórkowego, stabilności chromosomowej, aktywacji telomerów i apoptozy. Jednak kluczowym krokiem dla rozpoczęcia tumorogenezy wydaje się być integracja genomu wirusowego do genomu gospodarza.⁷⁴⁷⁵

Ciągła aktywność białek E6 i E7 prowadzi do aberracyjnej proliferacji komórek, akumulacji mutacji onkogenów i ostatecznie raka szyjki macicy. Wyciszenie E6 i E7 zmniejszało metylację genów supresorowych guza i odwracało fenotyp transformowany komórek raka szyjki macicy.⁷⁶

Przeważający mechanizm integracji polega na naprawie DNA z pośrednictwem mikrohomologii. Integracja HR-HPV ma liczne sposoby zmiany stanu komórek gospodarza, tym samym promując inicjację i rozwój nowotworów. Nadekspresja E6 i E7 ułatwia onkogenezę poprzez zakłócanie transkrypcji genów supresorowych guza i wyzwalanie amplifikacji genów flankujących.⁷⁷⁷⁸

Czasowy przebieg karcynogenezy

Proces rozwoju raka od infekcji HPV zajmuje co najmniej 5-10 lat i średnio 20-25 lat. Karcynogeneza szyjki macicy jest reprezentowana przez 4 przyczynowe etapy: nabycie HPV; przetrwanie HPV (vs. eliminacja); progresja do zmian przednowotworowych; rak inwazyjny.⁷⁹

Średni czas od infekcji HPV do CIN 3 wynosi 7-15 lat, osiągając szczyt w wieku 25-30 lat. Przejście do raka inwazyjnego jest wpływane przez HPV wysokiego ryzyka i niedojrzały nabłonek metaplastyczny strefy transformacji (TZ). Typ HPV jest najsilniejszym czynnikiem wpływającym na ryzyko przetrwania wirusa. HPV 16 jest wysoce karcynogenny z bezwzględnym ryzykiem CIN 3 zbliżającym się do 40% w ciągu 3-5 lat.⁸⁰

Podsumowanie i znaczenie kliniczne

Zakażenie wirusem brodawczaka ludzkiego (HPV) jest powszechnym problemem zdrowotnym, a zrozumienie jego patogenezy ma kluczowe znaczenie dla opracowania skutecznych strategii profilaktycznych i terapeutycznych. HPV infekuje komórki podstawne nabłonka wielowarstwowego płaskiego, początkowo wiążąc się z proteoglikanami siarczanu heparanu na błonie podstawnej odsłoniętej po urazie nabłonka. Po wniknięciu do komórki, wirus wykorzystuje maszynerię komórkową do replikacji swojego genomu i ekspresji białek wirusowych.⁸¹⁸²⁸³

Białka wirusowe E6 i E7 odgrywają kluczową rolę w patogenezie, modyfikując normalną fizjologię komórki poprzez interakcję z ważnymi regulatorami cyklu komórkowego, takimi jak p53 i pRb. To prowadzi do niekontrolowanej proliferacji, akumulacji mutacji genomowych i potencjalnie do transformacji nowotworowej. Integracja genomu HPV do genomu gospodarza jest decydującym krokiem w rozwoju raka szyjki macicy i innych nowotworów związanych z HPV.⁸⁴⁸⁵

HPV stosuje różne strategie unikania odpowiedzi immunologicznej, co może ostatecznie sprzyjać długotrwałemu utrzymywaniu się infekcji HPV i progresji raka szyjki macicy. Szczepionki oparte na cząstkach wirusopodobnych okazały się skuteczne w profilaktyce infekcji HPV i związanych z nią chorób, a zrozumienie mechanizmów patogenezy może prowadzić do opracowania nowych podejść terapeutycznych.⁸⁶⁸⁷

Pomimo znacznych postępów w zrozumieniu patogenezy HPV, wiele aspektów interakcji wirusa z gospodarzem pozostaje do wyjaśnienia. Dalsze badania nad mechanizmami unikania odpowiedzi immunologicznej, rolą kofaktorów w karcynogenezie i identyfikacją nowych celów terapeutycznych są konieczne do poprawy profilaktyki i leczenia infekcji HPV i związanych z nią chorób.⁸⁸⁸⁹

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Materiały źródłowe

#1 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
HPVs (human papillomaviruses) and other papillomaviruses have a unique mechanism of infection that has likely evolved to limit infection to the basal cells of stratified epithelium, the only tissue in which they replicate. Recent studies in a mouse cervicovaginal challenge model indicate that, surprisingly, the virus cannot initially bind to keratinocytes in vivo. Rather it must first bind via its L1 major capsid protein to heparan sulfate proteoglycans (HSPGs) on segments of the basement membrane (BM) exposed after epithelial trauma and undergo a conformational change that exposes the N-terminus of L2 minor capsid protein to furin cleavage. L2 proteolysis exposes a previously occluded surface of L1 that binds an as yet undetermined cell surface receptor on keratinocytes that have migrated over the BM to close the wound. Papillomaviruses are the only viruses that are known to initiate their infectious process at an extracellular site.
#2 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.
#3 Human Papillomavirus (HPV): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/219110-overview
Papillomaviruses are nonenveloped viruses with icosahedral symmetry, characterized by 72 capsomeres that enclose a genome of double-stranded circular DNA, approximately 8000 base pairs long. Their genome is divided into the following three major functional regions: […] HPV infects basal keratinocytes of the epidermis, typically through disruptions of the skin or mucosal surface. In this location, the virus remains latent as a circular episome in low copy numbers. Autoinoculation of the virus into adjacent lesions is common. HPV infection spreads through skin-associated contact rather than blood-borne transmission. Cell-mediated immunity (CMI) plays a significant role in wart regression; patients with CMI deficiency are particularly susceptible to HPV infection and are notoriously difficult to treat. […] HPV proteins E6 and E7 from high-risk serotypes have been shown to deactivate host tumor suppressor proteins p53 and Rb, leading to unregulated host cell proliferation and malignant transformation.
#4 Chapter 11: Human Papillomavirus | Pink Book | CDC
https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-11-human-papillomavirus.html?utm_source=chatgpt.com
HPV infection occurs at the basal epithelium. Although incidence of infection is high, most infections resolve spontaneously within a year or two. A small proportion of infected persons become persistently infected; persistent infection is the most important risk factor for the development of cervical cancer. […] High-risk or oncogenic HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers. High-risk types (including types 16, 18, and others) can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and anogenital cancers. High-risk HPV types are detected in 99% of cervical precancers. Type 16 is the cause of approximately 50% of cervical cancers worldwide, and types 16 and 18 together account for about 66% of cervical cancers. An additional five high-risk types, 31, 33, 45, 52, and 58, are responsible for another 15% of cervical cancers and 11% of all HPV-associated cancers. Infection with a high-risk HPV type is considered necessary for the development of cervical cancer but, by itself, is not sufficient to cause cancer. The vast majority of women with HPV infection, even those with high-risk HPV types, do not develop cancer.
#5 Human Papillomavirus (HPV): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/219110-overview
Papillomaviruses are nonenveloped viruses with icosahedral symmetry, characterized by 72 capsomeres that enclose a genome of double-stranded circular DNA, approximately 8000 base pairs long. Their genome is divided into the following three major functional regions: […] HPV infects basal keratinocytes of the epidermis, typically through disruptions of the skin or mucosal surface. In this location, the virus remains latent as a circular episome in low copy numbers. Autoinoculation of the virus into adjacent lesions is common. HPV infection spreads through skin-associated contact rather than blood-borne transmission. Cell-mediated immunity (CMI) plays a significant role in wart regression; patients with CMI deficiency are particularly susceptible to HPV infection and are notoriously difficult to treat. […] HPV proteins E6 and E7 from high-risk serotypes have been shown to deactivate host tumor suppressor proteins p53 and Rb, leading to unregulated host cell proliferation and malignant transformation.
#6 The Human Papillomavirus (HPV) in Human Pathology: Description, Pathogenesis, Oncogenic Role, Epidemiology and Detection Techniques
https://opendermatologyjournal.com/VOLUME/3/PAGE/90/ABSTRACT/
Persistent infection by human papilloma virus (HPV) is considered to be the main causative agent of cervical cancer and other anogenital cancers. Of more than 30 genotypes capable of infecting the anogenital tract it is estimated that, worldwide, HPV 16 and 18 cause 70 percent of the cervical cancers. […] According to their oncogenic risk, they are classified as low-risk HPV (LR-HPV) and high-risk HPV (HR-HPV). […] As is logical, epidemiological studies attribute important population variations to the prevalence and cause/effect of different viral types, however, there is no doubt about the high prevalence or involvement of types 16 and 18 in high level pathologies and carcinomas in our population.
#7
https://www.linkedin.com/pulse/hpv-mechanism-infection-opalbiopharma
The mechanism of infection for papillomaviruses (PVs) is intriguing and, in some respects, unusual. […] New understandings of this process point to the fact that many of its peculiar characteristics are adaptations to viral lifestyle traits, such as the restriction of the product life cycle to terminally differentiating stratified squamous epithelium and the capacity to postpone the induction of an effective immune response for an extended period. […] Human papillomaviruses (HPVs) and other papillomaviruses have an unusual mode of infection that most likely developed to restrict infection to the basal cells of stratified epithelium, the only tissue in which they multiply. […] The only viruses known to start their infectious phase at an extracellular location are papillomaviruses. […] Internalization, uncoating in late endosomes, escape from the endosome via an L2-dependent mechanism, and eventually trafficking of an L2-genome complex to particular subnuclear domains known as ND10 bodies, where viral gene transcription is started, are all caused by transfer to the secondary receptor.
#8 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
HPVs (human papillomaviruses) and other papillomaviruses have a unique mechanism of infection that has likely evolved to limit infection to the basal cells of stratified epithelium, the only tissue in which they replicate. Recent studies in a mouse cervicovaginal challenge model indicate that, surprisingly, the virus cannot initially bind to keratinocytes in vivo. Rather it must first bind via its L1 major capsid protein to heparan sulfate proteoglycans (HSPGs) on segments of the basement membrane (BM) exposed after epithelial trauma and undergo a conformational change that exposes the N-terminus of L2 minor capsid protein to furin cleavage. L2 proteolysis exposes a previously occluded surface of L1 that binds an as yet undetermined cell surface receptor on keratinocytes that have migrated over the BM to close the wound. Papillomaviruses are the only viruses that are known to initiate their infectious process at an extracellular site.
#9 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
HPVs (human papillomaviruses) and other papillomaviruses have a unique mechanism of infection that has likely evolved to limit infection to the basal cells of stratified epithelium, the only tissue in which they replicate. Recent studies in a mouse cervicovaginal challenge model indicate that, surprisingly, the virus cannot initially bind to keratinocytes in vivo. Rather it must first bind via its L1 major capsid protein to heparan sulfate proteoglycans (HSPGs) on segments of the basement membrane (BM) exposed after epithelial trauma and undergo a conformational change that exposes the N-terminus of L2 minor capsid protein to furin cleavage. L2 proteolysis exposes a previously occluded surface of L1 that binds an as yet undetermined cell surface receptor on keratinocytes that have migrated over the BM to close the wound. Papillomaviruses are the only viruses that are known to initiate their infectious process at an extracellular site.
#10 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text
https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11
As the primary etiological agents of cervical cancer, human papillomaviruses (HPVs) must deliver their genetic material into the nucleus of the target cell. The viral capsid has evolved to fulfil various roles that are critical to establish viral infection. The entry of HPV in vitro is initiated by binding to a cell surface receptor in contrast to the in vivo situation where the basement membrane has recently been identified as the primary site of virus binding. Binding of HPV triggers conformational changes, which affect both capsid proteins L1 and L2, and such changes are a prerequisite for interaction with the elusive uptake receptor. Most HPV types that have been examined, appear to enter the cell via a clathrin-dependent endocytic mechanism, although many data are inconclusive and inconsistent.
#11 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
HPVs (human papillomaviruses) and other papillomaviruses have a unique mechanism of infection that has likely evolved to limit infection to the basal cells of stratified epithelium, the only tissue in which they replicate. Recent studies in a mouse cervicovaginal challenge model indicate that, surprisingly, the virus cannot initially bind to keratinocytes in vivo. Rather it must first bind via its L1 major capsid protein to heparan sulfate proteoglycans (HSPGs) on segments of the basement membrane (BM) exposed after epithelial trauma and undergo a conformational change that exposes the N-terminus of L2 minor capsid protein to furin cleavage. L2 proteolysis exposes a previously occluded surface of L1 that binds an as yet undetermined cell surface receptor on keratinocytes that have migrated over the BM to close the wound. Papillomaviruses are the only viruses that are known to initiate their infectious process at an extracellular site.
#12 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text
https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11
The HPV genome is surrounded by an icosahedral capsid (T = 7) of 55 nm in diameter composed by two structural proteins, the major protein L1 and the minor capsid protein L2. The L2 protein is an internally located multifunctional protein with roles in genome encapsidation, L1 interaction and capsid stabilization, endosomal escape of virions and nuclear transport of the HPV genome. […] The classical notion of a virus binding to a single receptor to enter cells through a single defined uptake mechanism is quickly being overtaken by a more complex picture. New findings, such as a specific co-receptor and virus attachment to multiple receptors, have raised the question that viruses known to bind to a non-specific receptor may turn out to also have a more specific co-receptor. […] Taken together, capsid interaction with HSPG induces conformational changes that result in the exposure of the L2 amino terminus. Exposure of this L2 N-terminus allows access to highly conserved consensus furin convertase recognition site and subsequent furin cleavage which is essential for successful infection.
#13 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The life cycle of HPV is linked to the differentiation program of the infected host cell, the keratinocyte, with production of mature virion particles restricted to differentiated suprabasal cells. Infection by papillomaviruses is thought to occur through microwounds of the epithelium that expose cells in the basal layer to viral entry. The receptor for entry of the virus into cells is currently unknown; however, heparin sulfate mediates the initial attachment of virions to cells. Cells in the basal layer consist of stem cells and transit-amplifying cells that are continuously dividing and provide a reservoir of cells for the suprabasal regions. HPV infection of these cells leads to the activation of a cascade of viral gene expression that results in the production of approximately 20 to 100 extrachromosomal copies of viral DNA per cell. This average copy number is stably maintained in undifferentiated basal cells throughout the course of the infection. Among the first viral proteins to be expressed are the replication factors, E1 and E2. These proteins form a complex that binds to sequences at the viral origin of replication and acts to recruit cellular polymerases and accessory proteins to mediate replication. The E1 protein also exhibits helicase activity, allowing for the separation of viral DNA strands ahead of the replication complex. E2 is a site-specific DNA binding protein that helps to recruit E1 to the origin but also plays a role in regulating viral transcription from the early promoter.
#14 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text
https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11
The HPV genome is surrounded by an icosahedral capsid (T = 7) of 55 nm in diameter composed by two structural proteins, the major protein L1 and the minor capsid protein L2. The L2 protein is an internally located multifunctional protein with roles in genome encapsidation, L1 interaction and capsid stabilization, endosomal escape of virions and nuclear transport of the HPV genome. […] The classical notion of a virus binding to a single receptor to enter cells through a single defined uptake mechanism is quickly being overtaken by a more complex picture. New findings, such as a specific co-receptor and virus attachment to multiple receptors, have raised the question that viruses known to bind to a non-specific receptor may turn out to also have a more specific co-receptor. […] Taken together, capsid interaction with HSPG induces conformational changes that result in the exposure of the L2 amino terminus. Exposure of this L2 N-terminus allows access to highly conserved consensus furin convertase recognition site and subsequent furin cleavage which is essential for successful infection.
#15 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
After initial binding to HSPGs and furin cleavage, the virus is transferred to an unidentified receptor on the cell surface. The virus then enters the cell via an endocytic pathway and within 4 h localizes in the early endosome. By 12 h, the virus uncoats within the late endosome, and the viral genome complexed with L2 is released. […] After endosome escape, both the fate of L1 and the mechanism by which the L2-genome complex traffic through the cytoplasm and into the nucleus are poorly understood. […] Localization at ND10 promotes transcription of the viral genome. This positive function of ND10 domains in the PV life cycle contrasts with the evidence that herpes and other DNA viruses target PML for degradation because ND10s function to inhibit viral replication. […] The exceptional effectiveness of L1 and L2 neutralizing antibodies in preventing in vivo infection is likely due, at least in part, to the lengthy exposure of neutralizing epitopes while the virus resides on the BM and cell surface.
#16 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text
https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11
HPVs are generally internalized via a clathrin-dependent endocytic mechanism, which is initially dependent on actin. Some HPV types may use alternative uptake pathways to enter cells, such as a caveolae-dependent route or the involvement of tetraspanin-enriched domains as a platform for viral uptake.
#17 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text
https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11
HPVs are generally internalized via a clathrin-dependent endocytic mechanism, which is initially dependent on actin. Some HPV types may use alternative uptake pathways to enter cells, such as a caveolae-dependent route or the involvement of tetraspanin-enriched domains as a platform for viral uptake.
#18 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
After initial binding to HSPGs and furin cleavage, the virus is transferred to an unidentified receptor on the cell surface. The virus then enters the cell via an endocytic pathway and within 4 h localizes in the early endosome. By 12 h, the virus uncoats within the late endosome, and the viral genome complexed with L2 is released. […] After endosome escape, both the fate of L1 and the mechanism by which the L2-genome complex traffic through the cytoplasm and into the nucleus are poorly understood. […] Localization at ND10 promotes transcription of the viral genome. This positive function of ND10 domains in the PV life cycle contrasts with the evidence that herpes and other DNA viruses target PML for degradation because ND10s function to inhibit viral replication. […] The exceptional effectiveness of L1 and L2 neutralizing antibodies in preventing in vivo infection is likely due, at least in part, to the lengthy exposure of neutralizing epitopes while the virus resides on the BM and cell surface.
#19
https://www.linkedin.com/pulse/hpv-mechanism-infection-opalbiopharma
The mechanism of infection for papillomaviruses (PVs) is intriguing and, in some respects, unusual. […] New understandings of this process point to the fact that many of its peculiar characteristics are adaptations to viral lifestyle traits, such as the restriction of the product life cycle to terminally differentiating stratified squamous epithelium and the capacity to postpone the induction of an effective immune response for an extended period. […] Human papillomaviruses (HPVs) and other papillomaviruses have an unusual mode of infection that most likely developed to restrict infection to the basal cells of stratified epithelium, the only tissue in which they multiply. […] The only viruses known to start their infectious phase at an extracellular location are papillomaviruses. […] Internalization, uncoating in late endosomes, escape from the endosome via an L2-dependent mechanism, and eventually trafficking of an L2-genome complex to particular subnuclear domains known as ND10 bodies, where viral gene transcription is started, are all caused by transfer to the secondary receptor.
#20 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
HPVs (human papillomaviruses) and other papillomaviruses have a unique mechanism of infection that has likely evolved to limit infection to the basal cells of stratified epithelium, the only tissue in which they replicate. Recent studies in a mouse cervicovaginal challenge model indicate that, surprisingly, the virus cannot initially bind to keratinocytes in vivo. Rather it must first bind via its L1 major capsid protein to heparan sulfate proteoglycans (HSPGs) on segments of the basement membrane (BM) exposed after epithelial trauma and undergo a conformational change that exposes the N-terminus of L2 minor capsid protein to furin cleavage. L2 proteolysis exposes a previously occluded surface of L1 that binds an as yet undetermined cell surface receptor on keratinocytes that have migrated over the BM to close the wound. Papillomaviruses are the only viruses that are known to initiate their infectious process at an extracellular site.
#21 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
After initial binding to HSPGs and furin cleavage, the virus is transferred to an unidentified receptor on the cell surface. The virus then enters the cell via an endocytic pathway and within 4 h localizes in the early endosome. By 12 h, the virus uncoats within the late endosome, and the viral genome complexed with L2 is released. […] After endosome escape, both the fate of L1 and the mechanism by which the L2-genome complex traffic through the cytoplasm and into the nucleus are poorly understood. […] Localization at ND10 promotes transcription of the viral genome. This positive function of ND10 domains in the PV life cycle contrasts with the evidence that herpes and other DNA viruses target PML for degradation because ND10s function to inhibit viral replication. […] The exceptional effectiveness of L1 and L2 neutralizing antibodies in preventing in vivo infection is likely due, at least in part, to the lengthy exposure of neutralizing epitopes while the virus resides on the BM and cell surface.
#22 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.
#23 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The life cycle of HPV is linked to the differentiation program of the infected host cell, the keratinocyte, with production of mature virion particles restricted to differentiated suprabasal cells. Infection by papillomaviruses is thought to occur through microwounds of the epithelium that expose cells in the basal layer to viral entry. The receptor for entry of the virus into cells is currently unknown; however, heparin sulfate mediates the initial attachment of virions to cells. Cells in the basal layer consist of stem cells and transit-amplifying cells that are continuously dividing and provide a reservoir of cells for the suprabasal regions. HPV infection of these cells leads to the activation of a cascade of viral gene expression that results in the production of approximately 20 to 100 extrachromosomal copies of viral DNA per cell. This average copy number is stably maintained in undifferentiated basal cells throughout the course of the infection. Among the first viral proteins to be expressed are the replication factors, E1 and E2. These proteins form a complex that binds to sequences at the viral origin of replication and acts to recruit cellular polymerases and accessory proteins to mediate replication. The E1 protein also exhibits helicase activity, allowing for the separation of viral DNA strands ahead of the replication complex. E2 is a site-specific DNA binding protein that helps to recruit E1 to the origin but also plays a role in regulating viral transcription from the early promoter.
#24 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The life cycle of HPV is linked to the differentiation program of the infected host cell, the keratinocyte, with production of mature virion particles restricted to differentiated suprabasal cells. Infection by papillomaviruses is thought to occur through microwounds of the epithelium that expose cells in the basal layer to viral entry. The receptor for entry of the virus into cells is currently unknown; however, heparin sulfate mediates the initial attachment of virions to cells. Cells in the basal layer consist of stem cells and transit-amplifying cells that are continuously dividing and provide a reservoir of cells for the suprabasal regions. HPV infection of these cells leads to the activation of a cascade of viral gene expression that results in the production of approximately 20 to 100 extrachromosomal copies of viral DNA per cell. This average copy number is stably maintained in undifferentiated basal cells throughout the course of the infection. Among the first viral proteins to be expressed are the replication factors, E1 and E2. These proteins form a complex that binds to sequences at the viral origin of replication and acts to recruit cellular polymerases and accessory proteins to mediate replication. The E1 protein also exhibits helicase activity, allowing for the separation of viral DNA strands ahead of the replication complex. E2 is a site-specific DNA binding protein that helps to recruit E1 to the origin but also plays a role in regulating viral transcription from the early promoter.
#25 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The life cycle of HPV is linked to the differentiation program of the infected host cell, the keratinocyte, with production of mature virion particles restricted to differentiated suprabasal cells. Infection by papillomaviruses is thought to occur through microwounds of the epithelium that expose cells in the basal layer to viral entry. The receptor for entry of the virus into cells is currently unknown; however, heparin sulfate mediates the initial attachment of virions to cells. Cells in the basal layer consist of stem cells and transit-amplifying cells that are continuously dividing and provide a reservoir of cells for the suprabasal regions. HPV infection of these cells leads to the activation of a cascade of viral gene expression that results in the production of approximately 20 to 100 extrachromosomal copies of viral DNA per cell. This average copy number is stably maintained in undifferentiated basal cells throughout the course of the infection. Among the first viral proteins to be expressed are the replication factors, E1 and E2. These proteins form a complex that binds to sequences at the viral origin of replication and acts to recruit cellular polymerases and accessory proteins to mediate replication. The E1 protein also exhibits helicase activity, allowing for the separation of viral DNA strands ahead of the replication complex. E2 is a site-specific DNA binding protein that helps to recruit E1 to the origin but also plays a role in regulating viral transcription from the early promoter.
#26
#27 Human Papillomavirus (HPV) – Definition, Structure, Genome, Replication, Pathogenesis, Treatment – Biology Notes Online
https://biologynotesonline.com/human-papillomavirus-hpv-definition-structure-genome-replication-pathogenesis-treatment/
To activate papillomavirus DNA replication, both E1 and E2 proteins are necessary. Initially, E1 as a dimer and E2 as a dimer bind to the viral origin, resulting to the formation of an E1E2 ternary complex that inhibits the nonspecific binding of E1-DNA. […] Throughout the periods of plasmid and episomal maintenance, viral gene expression is limited. During the typical HPV life cycle, the expression of multiple viral oncogenes, including the E6 and E7 proteins, is tightly regulated. […] The characteristics of HPVs life cycle play a crucial role in avoiding immune system detection and viral pathogenicity. HPVs life cycle is distinguished by nonlytic immunity of infected cells and the absence of viremia and inflammatory signals.
#28 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The E6 and E7 proteins of the high-risk HPV types act as viral oncoproteins, but no such functions are associated with the corresponding proteins from the low-risk types. High-risk E6 binds the p53 tumor suppressor protein as part of a trimeric complex with the cellular ubiquitin ligase, E6AP, leading to the rapid turnover of p53. E7 binds to the retinoblastoma (Rb) family of tumor suppressors, as well as other proteins involved in cell cycle regulation. As HPV infected basal cells divide, viral genomes are partitioned into daughter cells, one of which detaches from the basal layer, migrates toward the stratum granulosum, and undergoes differentiation. In normal uninfected epithelia, cells exit the cell cycle as they leave the basal layer, and this often results in the loss of nuclei in suprabasal cells. As infected cells leave the basal layer, they remain active in the cell cycle due to action of the E7 protein. Cells reenter the S phase in highly differentiated cells and activate the expression of cellular replication factors required for viral replication. The presence of E7 leads to a characteristic retention of nuclei throughout all layers of infected epithelia. Not only are the viral oncoproteins necessary for cell immortalization and retention of cell cycle capability on differentiation, but E6 and E7 have also been shown to be necessary for the maintenance of extrachromosomal forms of HPV in undifferentiated basal cells. The mechanism by which this occurs is not clear, although it probably likely involves abrogation of checkpoints that block the long-term retention of the extrachromosomal DNAs.
#29 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The E6 and E7 proteins of the high-risk HPV types act as viral oncoproteins, but no such functions are associated with the corresponding proteins from the low-risk types. High-risk E6 binds the p53 tumor suppressor protein as part of a trimeric complex with the cellular ubiquitin ligase, E6AP, leading to the rapid turnover of p53. E7 binds to the retinoblastoma (Rb) family of tumor suppressors, as well as other proteins involved in cell cycle regulation. As HPV infected basal cells divide, viral genomes are partitioned into daughter cells, one of which detaches from the basal layer, migrates toward the stratum granulosum, and undergoes differentiation. In normal uninfected epithelia, cells exit the cell cycle as they leave the basal layer, and this often results in the loss of nuclei in suprabasal cells. As infected cells leave the basal layer, they remain active in the cell cycle due to action of the E7 protein. Cells reenter the S phase in highly differentiated cells and activate the expression of cellular replication factors required for viral replication. The presence of E7 leads to a characteristic retention of nuclei throughout all layers of infected epithelia. Not only are the viral oncoproteins necessary for cell immortalization and retention of cell cycle capability on differentiation, but E6 and E7 have also been shown to be necessary for the maintenance of extrachromosomal forms of HPV in undifferentiated basal cells. The mechanism by which this occurs is not clear, although it probably likely involves abrogation of checkpoints that block the long-term retention of the extrachromosomal DNAs.
#30 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The most likely mechanism centers on the activation of expression of the late viral promoter, resulting in high-level expression of transcripts encoding the viral replication proteins, E1 and E2, along with the late genes. Unlike the early promoter, the late promoter is not negatively regulated by E2 protein, and high levels of expression occur upon differentiation, leading to amplification of viral DNA. This increase in template numbers results in a further increase in expression of the replication proteins. It is possible that cellular or other viral factors are upregulated on differentiation and that these factors contribute to activation of late functions, but the identification of these proteins is only beginning. In low-grade infections, the high-risk HPV genomes are present as episomes, while during progression to high-grade lesions or carcinomas, the genome often is found integrated into host sequences. This integration usually occurs within the E2 ORF and results in loss of E2 repressive action leading to higher levels of E6 and E7 expression.
#31 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The most likely mechanism centers on the activation of expression of the late viral promoter, resulting in high-level expression of transcripts encoding the viral replication proteins, E1 and E2, along with the late genes. Unlike the early promoter, the late promoter is not negatively regulated by E2 protein, and high levels of expression occur upon differentiation, leading to amplification of viral DNA. This increase in template numbers results in a further increase in expression of the replication proteins. It is possible that cellular or other viral factors are upregulated on differentiation and that these factors contribute to activation of late functions, but the identification of these proteins is only beginning. In low-grade infections, the high-risk HPV genomes are present as episomes, while during progression to high-grade lesions or carcinomas, the genome often is found integrated into host sequences. This integration usually occurs within the E2 ORF and results in loss of E2 repressive action leading to higher levels of E6 and E7 expression.
#32 HPV InfectionsâClassification, Pathogenesis, and Potential New Therapies
https://www.mdpi.com/1422-0067/25/14/7616
E7 binds to the retinoblastoma tumor suppressor protein pRb and to smaller proteins such as p107 and p130, inhibiting their action and, in the case of oncogenic HPV, leading to accelerated degradation. […] In most cases of HPV infection, the DNA remains in an episomal form, unintegrated into the host DNA, allowing the virus to replicate efficiently. […] The integration of the HPV genome into the cellular genome has been demonstrated to play a crucial role in the development of cancer. […] The E5 protein is responsible for the control of cell growth, differentiation, and immune modulation. […] The viral proteins act by increasing the expression of the catalytic subunit of telomerase, so-called human telomerase reverse transcriptase (hTERT). […] The association of E6 with PDZ may play roles in sustaining epithelial cell proliferation and the HPV replication cycle and also in tumor transformation. […] The effectiveness of treatment may be enhanced by the inclusion of methods which are based on the stimulation of the immune system in the fight against infection.
#33 HPV InfectionsâClassification, Pathogenesis, and Potential New Therapies
https://www.mdpi.com/1422-0067/25/14/7616
E7 binds to the retinoblastoma tumor suppressor protein pRb and to smaller proteins such as p107 and p130, inhibiting their action and, in the case of oncogenic HPV, leading to accelerated degradation. […] In most cases of HPV infection, the DNA remains in an episomal form, unintegrated into the host DNA, allowing the virus to replicate efficiently. […] The integration of the HPV genome into the cellular genome has been demonstrated to play a crucial role in the development of cancer. […] The E5 protein is responsible for the control of cell growth, differentiation, and immune modulation. […] The viral proteins act by increasing the expression of the catalytic subunit of telomerase, so-called human telomerase reverse transcriptase (hTERT). […] The association of E6 with PDZ may play roles in sustaining epithelial cell proliferation and the HPV replication cycle and also in tumor transformation. […] The effectiveness of treatment may be enhanced by the inclusion of methods which are based on the stimulation of the immune system in the fight against infection.
#34 SciELO Brazil – Update on human papilloma virus – part I: epidemiology, pathogenesis, and clinical spectrum^,^, Update on human papilloma virus – part I: epidemiology, pathogenesis, and clinical spectrumhttps://www.scielo.br/j/abd/a/ZZtwyNTQsx3RfBfhpctD8rt/
They are a group of viruses with marked species-specificity and are capable of producing subclinical infections, of long evolution with low viral replication; clinical infections, through the evasion of the hosts immune mechanisms; in addition, they participate in the process of carcinogenesis of tumors of the cutaneous, anogenital, and oral region. […] The E6 protein of HPVs 5, 8, and 38, for example, allows the infected cell to accumulate genetic mutations necessary for the process of carcinogenesis by interfering with cellular defense mechanisms. […] The mechanism by which HR -HPVs participate in oncogenesis includes a deregulation in viral gene expression, which is caused by the integration of the viral genome in high-grade premalignant lesions and co-expression of proteins E6 and E7.
#35 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
The degradation of p53 by E6 is important because p53 is a transcription factor that regulates the expression of genes encoding regulators of cell cycle, DNA repair machinery, metabolism and apoptosis. […] Recent studies indicate the existence of an intricate HPV interactome, i.e., a network of intermolecular interactions of E6 and E7 with the host cell proteins. […] Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). […] The viral oncoproteins E6 and E7 are known to induce DNA damage, centrosome abnormalities and chromosomal segregation defects, thereby leading to chromosomal instability.
#36 HPV InfectionsâClassification, Pathogenesis, and Potential New Therapies
https://www.mdpi.com/1422-0067/25/14/7616
HPVs are resistant to many disinfectants and relatively unsusceptible to external conditions. […] This paper presents the systematics of HPV and the differences in HPV structure between different genetic types, lineages, and sublineages, based on the literature and GenBank data. We also present the pathogenesis of diseases caused by HPV, with a special focus on the role played by E6, E7, and other viral proteins in the development of benign and cancerous lesions. […] Early viral proteins such as E5, E6, and E7 play the most important role in the pathogenesis of neoplastic lesions arising from HPV infections. […] The E6 protein (150â160 amino acids, about 18 kDal) is a major oncoprotein. It inhibits apoptosis and differentiation. It affects cell shape, polarity, mobility, and signaling.
#37 Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity
https://www.periodicos.capes.gov.br/index.php/acervo/buscador.html?task=detalhes&id=W2100448174
Human papillomaviruses (HPVs) are small doublestranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPVinduced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control.
#38 Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity
https://www.periodicos.capes.gov.br/index.php/acervo/buscador.html?task=detalhes&id=W2100448174
Human papillomaviruses (HPVs) are small doublestranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPVinduced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control.
#39 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The E6 and E7 proteins of the high-risk HPV types act as viral oncoproteins, but no such functions are associated with the corresponding proteins from the low-risk types. High-risk E6 binds the p53 tumor suppressor protein as part of a trimeric complex with the cellular ubiquitin ligase, E6AP, leading to the rapid turnover of p53. E7 binds to the retinoblastoma (Rb) family of tumor suppressors, as well as other proteins involved in cell cycle regulation. As HPV infected basal cells divide, viral genomes are partitioned into daughter cells, one of which detaches from the basal layer, migrates toward the stratum granulosum, and undergoes differentiation. In normal uninfected epithelia, cells exit the cell cycle as they leave the basal layer, and this often results in the loss of nuclei in suprabasal cells. As infected cells leave the basal layer, they remain active in the cell cycle due to action of the E7 protein. Cells reenter the S phase in highly differentiated cells and activate the expression of cellular replication factors required for viral replication. The presence of E7 leads to a characteristic retention of nuclei throughout all layers of infected epithelia. Not only are the viral oncoproteins necessary for cell immortalization and retention of cell cycle capability on differentiation, but E6 and E7 have also been shown to be necessary for the maintenance of extrachromosomal forms of HPV in undifferentiated basal cells. The mechanism by which this occurs is not clear, although it probably likely involves abrogation of checkpoints that block the long-term retention of the extrachromosomal DNAs.
#40 HPV InfectionsâClassification, Pathogenesis, and Potential New Therapies
https://www.mdpi.com/1422-0067/25/14/7616
HPVs are resistant to many disinfectants and relatively unsusceptible to external conditions. […] This paper presents the systematics of HPV and the differences in HPV structure between different genetic types, lineages, and sublineages, based on the literature and GenBank data. We also present the pathogenesis of diseases caused by HPV, with a special focus on the role played by E6, E7, and other viral proteins in the development of benign and cancerous lesions. […] Early viral proteins such as E5, E6, and E7 play the most important role in the pathogenesis of neoplastic lesions arising from HPV infections. […] The E6 protein (150â160 amino acids, about 18 kDal) is a major oncoprotein. It inhibits apoptosis and differentiation. It affects cell shape, polarity, mobility, and signaling.
#41 Human papillomavirus infection – Wikipedia
https://en.wikipedia.org/wiki/Human_papillomavirus_infection
E6 produces a protein (also called E6) that simultaneously binds to two host cell proteins called p53 and E6-Associated Protein (E6-AP). E6AP is an E3 Ubiquitin ligase, an enzyme whose purpose is to tag proteins with a post-translational modification called Ubiquitin. By binding both proteins, E6 induces E6AP to attach a chain of ubiquitin molecules to p53, thereby flagging p53 for proteosomal degradation. Normally, p53 acts to prevent cell growth and promotes cell death in the presence of DNA damage. p53 also upregulates the p21 protein, which blocks the formation of the cyclin D/Cdk4 complex, thereby preventing the phosphorylation of retinoblastoma protein (RB), and in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor-suppressor protein that arrests the cell cycle and prevents cell growth and survival when DNA damage occurs. Thus, the degradation of p53, induced by E6, promotes unregulated cell division, cell growth and cell survival, all characteristics of cancer.
#42 HPV InfectionsâClassification, Pathogenesis, and Potential New Therapies
https://www.mdpi.com/1422-0067/25/14/7616
E7 binds to the retinoblastoma tumor suppressor protein pRb and to smaller proteins such as p107 and p130, inhibiting their action and, in the case of oncogenic HPV, leading to accelerated degradation. […] In most cases of HPV infection, the DNA remains in an episomal form, unintegrated into the host DNA, allowing the virus to replicate efficiently. […] The integration of the HPV genome into the cellular genome has been demonstrated to play a crucial role in the development of cancer. […] The E5 protein is responsible for the control of cell growth, differentiation, and immune modulation. […] The viral proteins act by increasing the expression of the catalytic subunit of telomerase, so-called human telomerase reverse transcriptase (hTERT). […] The association of E6 with PDZ may play roles in sustaining epithelial cell proliferation and the HPV replication cycle and also in tumor transformation. […] The effectiveness of treatment may be enhanced by the inclusion of methods which are based on the stimulation of the immune system in the fight against infection.
#43 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
The E7 protein can also directly interact with E2F1 in a retinoblastoma-independent manner in an in vitro and in vivo study, in which the E7 protein generated by the HR-HPVs binds more tightly to E2F1 than to LR-HPVs and activates E2F1-dependent transcription and promoter activities, which participate in the deregulation of the cell cycle and induction of transformation. […] HPV uses a variety of immune evasion mechanisms to suppress immune responses and promote cancer progression. […] HPV can show an immune escape strategy not only by hiding itself from recognition by immune cells by downregulating viral antigens, but also by disturbing the expression of immune response proteins, which further encourages prolonged viral persistence. […] HPV can acquire all these strategies to evade an effective immune response, which may eventually support the prolonged persistence of HPV infection and cervical cancer progression.
#44 HPV InfectionsâClassification, Pathogenesis, and Potential New Therapies
https://www.mdpi.com/1422-0067/25/14/7616
E7 binds to the retinoblastoma tumor suppressor protein pRb and to smaller proteins such as p107 and p130, inhibiting their action and, in the case of oncogenic HPV, leading to accelerated degradation. […] In most cases of HPV infection, the DNA remains in an episomal form, unintegrated into the host DNA, allowing the virus to replicate efficiently. […] The integration of the HPV genome into the cellular genome has been demonstrated to play a crucial role in the development of cancer. […] The E5 protein is responsible for the control of cell growth, differentiation, and immune modulation. […] The viral proteins act by increasing the expression of the catalytic subunit of telomerase, so-called human telomerase reverse transcriptase (hTERT). […] The association of E6 with PDZ may play roles in sustaining epithelial cell proliferation and the HPV replication cycle and also in tumor transformation. […] The effectiveness of treatment may be enhanced by the inclusion of methods which are based on the stimulation of the immune system in the fight against infection.
#45 Pathogenesis of Human Papillomavirus â Immunological Responses to HPV Infection | IntechOpen
https://www.intechopen.com/chapters/51256
Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. […] Infections by high-risk human papillomaviruses (HPVs) have been implicated as causative agents in a variety of cancers such as anogenital, and head and neck cancers. HPVs appear to have evolved mechanisms resulting in escape from host immune surveillance and delay of resolution of infection. […] The HPV E5 oncoprotein is one of the possible effectors that allows the virus to escape from host immune system through the downregulation of surface classical major histocompatibility complex class I (MHC I) and not the nonclassical MHC I. Lack of classical MHC I in infected cells expressing E5 would allow evasion of cytotoxic T lymphocytes (CTLs) killing and thus establishment and persistence of viral infection.
#46 Pathogenesis of Human Papillomavirus â Immunological Responses to HPV Infection | IntechOpen
https://www.intechopen.com/chapters/51256
Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. […] Infections by high-risk human papillomaviruses (HPVs) have been implicated as causative agents in a variety of cancers such as anogenital, and head and neck cancers. HPVs appear to have evolved mechanisms resulting in escape from host immune surveillance and delay of resolution of infection. […] The HPV E5 oncoprotein is one of the possible effectors that allows the virus to escape from host immune system through the downregulation of surface classical major histocompatibility complex class I (MHC I) and not the nonclassical MHC I. Lack of classical MHC I in infected cells expressing E5 would allow evasion of cytotoxic T lymphocytes (CTLs) killing and thus establishment and persistence of viral infection.
#47 Pathogenesis of Human Papillomavirus â Immunological Responses to HPV Infection | IntechOpen
https://www.intechopen.com/chapters/51256
HPV facilitates this mechanism using early oncoproteins, E5, E6 and E7, which have the ability to interfere and actively participate to the downregulation of host immune system. […] The downregulation of MHC class I by E5 oncoprotein allows the infected cell to evade cell-mediated immune response and this potentially enables other HPV oncoproteins in the establishment and persistence of virus infection. […] The downregulation of MHC I is an imperative mechanism to evade CTL-mediated immune clearance, however, the lack of surface MHC I will activate NK cells to attack and destroy the infected cells.
#48 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.
#49 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
The life cycle of HPV is linked to the differentiation program of the infected host cell, the keratinocyte, with production of mature virion particles restricted to differentiated suprabasal cells. Infection by papillomaviruses is thought to occur through microwounds of the epithelium that expose cells in the basal layer to viral entry. The receptor for entry of the virus into cells is currently unknown; however, heparin sulfate mediates the initial attachment of virions to cells. Cells in the basal layer consist of stem cells and transit-amplifying cells that are continuously dividing and provide a reservoir of cells for the suprabasal regions. HPV infection of these cells leads to the activation of a cascade of viral gene expression that results in the production of approximately 20 to 100 extrachromosomal copies of viral DNA per cell. This average copy number is stably maintained in undifferentiated basal cells throughout the course of the infection. Among the first viral proteins to be expressed are the replication factors, E1 and E2. These proteins form a complex that binds to sequences at the viral origin of replication and acts to recruit cellular polymerases and accessory proteins to mediate replication. The E1 protein also exhibits helicase activity, allowing for the separation of viral DNA strands ahead of the replication complex. E2 is a site-specific DNA binding protein that helps to recruit E1 to the origin but also plays a role in regulating viral transcription from the early promoter.
#50 Pathogenesis of HPV-transformed cells – ATB – Applied Tumor Biology, University Hospital Heidelberg
https://atb-heidelberg.de/projects/hpv-projects/hpvcancerpathogenesis/
Upon infection of the epithelium by HPV different infection stages can be distinguished, that are termed latent, permissive and transforming stage. […] In the latent infection stage, HPV generally resides in the cells at very low copy numbers without considerable viral gene expression. […] A small proportion of individuals that are infected with a high-risk HPV type may experience the development of a transforming HPV infection stage. This transforming stage is characterized by the substantial overexpression of the viral oncoproteins E6 and E7, which represent the central drivers for HPV-related cancer development and maintenance. […] The uncontrolled expression of the E6 and E7 oncogenes is primarily driven by a loss of the regulatory function of the viral E2 protein. […] Research in our department and by other groups demonstrated an important mechanism how a loss of E2 function and subsequent E6/E7 overexpression may arise.
#51 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
Human papillomavirus (HPV) is implicated in over 90% of cervical cancer cases, with factors like regional variability, HPV genotype, the population studied, HPV vaccination status, and anatomical sample collection location influencing the prevalence and pathology of HPV-induced cancer. […] The oncogenic ability of HPV is not only sufficient for the progression of malignancy, but also for other tumor-generating steps required for the production of invasive cancer, such as coinfection with other viruses, lifestyle factors such as high parity, smoking, tobacco chewing, use of contraceptives for a long time, and immune responses such as stimulation of chronic stromal inflammation and immune deviation in the tumor microenvironment. […] Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types.
#52 Mechanisms of cell entry by human papillomaviruses: an overview | Virology Journal | Full Text
https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-7-11
The HPV genome is surrounded by an icosahedral capsid (T = 7) of 55 nm in diameter composed by two structural proteins, the major protein L1 and the minor capsid protein L2. The L2 protein is an internally located multifunctional protein with roles in genome encapsidation, L1 interaction and capsid stabilization, endosomal escape of virions and nuclear transport of the HPV genome. […] The classical notion of a virus binding to a single receptor to enter cells through a single defined uptake mechanism is quickly being overtaken by a more complex picture. New findings, such as a specific co-receptor and virus attachment to multiple receptors, have raised the question that viruses known to bind to a non-specific receptor may turn out to also have a more specific co-receptor. […] Taken together, capsid interaction with HSPG induces conformational changes that result in the exposure of the L2 amino terminus. Exposure of this L2 N-terminus allows access to highly conserved consensus furin convertase recognition site and subsequent furin cleavage which is essential for successful infection.
#53 Human papillomavirus infections: Epidemiology and disease associations – UpToDate
https://www.uptodate.com/contents/human-papillomavirus-infections-epidemiology-and-disease-associations
Papillomaviruses are double-stranded deoxyribonucleic acid (DNA) viruses that constitute the Papillomavirus genus of the Papillomaviridae family. […] The role of HPV in the pathogenesis of epithelial cancers is discussed elsewhere. […] The L2 is the minor capsid protein that along with L1 mediates HPV infectivity.
#54 Human Papillomavirus (HPV) Vaccines – NCI
https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet
HPV vaccines protect against infection with human papillomaviruses (HPV). HPV is a group of more than 200 related viruses, of which more than 40 are spread through direct sexual contact. Among these, two HPV types cause genital warts, and about a dozen HPV types can cause certain types of cancercervical, anal, oropharyngeal, penile, vulvar, and vaginal. […] Clinical trials have shown that HPV vaccines are highly effective in preventing cervical infection with the types of HPV they target when given before first exposure to the virusthat is, before individuals begin to engage in sexual activity. HPV vaccines have also been found to reduce infections in other tissues that HPV infects, including the anus and oral region. […] The current HPV vaccines are based on virus-like particles (VLPs) that are formed by HPV surface components. VLPs are not infectious because they lack the viruss DNA. However, they closely resemble the natural virus, and antibodies against the VLPs also have activity against the natural virus. The VLPs have been found to be strongly immunogenic, which means that they induce high levels of antibody production by the body. This makes the vaccines highly effective.
#55 Pathogenesis of Human Papillomavirus â Immunological Responses to HPV Infection | IntechOpen
https://www.intechopen.com/chapters/51256
Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. […] Infections by high-risk human papillomaviruses (HPVs) have been implicated as causative agents in a variety of cancers such as anogenital, and head and neck cancers. HPVs appear to have evolved mechanisms resulting in escape from host immune surveillance and delay of resolution of infection. […] The HPV E5 oncoprotein is one of the possible effectors that allows the virus to escape from host immune system through the downregulation of surface classical major histocompatibility complex class I (MHC I) and not the nonclassical MHC I. Lack of classical MHC I in infected cells expressing E5 would allow evasion of cytotoxic T lymphocytes (CTLs) killing and thus establishment and persistence of viral infection.
#56 Human Papillomavirus (HPV) – Definition, Structure, Genome, Replication, Pathogenesis, Treatment – Biology Notes Online
https://biologynotesonline.com/human-papillomavirus-hpv-definition-structure-genome-replication-pathogenesis-treatment/
To activate papillomavirus DNA replication, both E1 and E2 proteins are necessary. Initially, E1 as a dimer and E2 as a dimer bind to the viral origin, resulting to the formation of an E1E2 ternary complex that inhibits the nonspecific binding of E1-DNA. […] Throughout the periods of plasmid and episomal maintenance, viral gene expression is limited. During the typical HPV life cycle, the expression of multiple viral oncogenes, including the E6 and E7 proteins, is tightly regulated. […] The characteristics of HPVs life cycle play a crucial role in avoiding immune system detection and viral pathogenicity. HPVs life cycle is distinguished by nonlytic immunity of infected cells and the absence of viremia and inflammatory signals.
#57 Pathogenesis of Human Papillomavirus â Immunological Responses to HPV Infection | IntechOpen
https://www.intechopen.com/chapters/51256
The lifecycle, oncogenic characteristics and molecular-based evidence of HR-HPVs are suggestive of a causal role for cancer. HPV infections are normally cleared by the immune system; however, the persistence of HPV could trigger a progression to malignant lesion in the presence of other risk factors. […] Therefore, the establishment, persistence of HR-HPV infection and evasion of the host immune system are necessary for premalignant lesions to initiate and progress towards squamous carcinoma. […] The suppression of HPV-induced lesion depends on the host inflammatory reaction and penetration of lymphocytes to the infected tissue. […] The nonlytic feature of HPV is one of the explanations for evading the recognition of HPV infection. HPV does not lyse the infected cell or cause viremia, and this will reduce the exposure of viral antigen to cell-mediated immunity and consequent lack of inflammation.
#58 Pathogenesis of Human Papillomavirus â Immunological Responses to HPV Infection | IntechOpen
https://www.intechopen.com/chapters/51256
HPV facilitates this mechanism using early oncoproteins, E5, E6 and E7, which have the ability to interfere and actively participate to the downregulation of host immune system. […] The downregulation of MHC class I by E5 oncoprotein allows the infected cell to evade cell-mediated immune response and this potentially enables other HPV oncoproteins in the establishment and persistence of virus infection. […] The downregulation of MHC I is an imperative mechanism to evade CTL-mediated immune clearance, however, the lack of surface MHC I will activate NK cells to attack and destroy the infected cells.
#59 Pathogenesis of Human Papillomavirus â Immunological Responses to HPV Infection | IntechOpen
https://www.intechopen.com/chapters/51256
HPV facilitates this mechanism using early oncoproteins, E5, E6 and E7, which have the ability to interfere and actively participate to the downregulation of host immune system. […] The downregulation of MHC class I by E5 oncoprotein allows the infected cell to evade cell-mediated immune response and this potentially enables other HPV oncoproteins in the establishment and persistence of virus infection. […] The downregulation of MHC I is an imperative mechanism to evade CTL-mediated immune clearance, however, the lack of surface MHC I will activate NK cells to attack and destroy the infected cells.
#60 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
The E7 protein can also directly interact with E2F1 in a retinoblastoma-independent manner in an in vitro and in vivo study, in which the E7 protein generated by the HR-HPVs binds more tightly to E2F1 than to LR-HPVs and activates E2F1-dependent transcription and promoter activities, which participate in the deregulation of the cell cycle and induction of transformation. […] HPV uses a variety of immune evasion mechanisms to suppress immune responses and promote cancer progression. […] HPV can show an immune escape strategy not only by hiding itself from recognition by immune cells by downregulating viral antigens, but also by disturbing the expression of immune response proteins, which further encourages prolonged viral persistence. […] HPV can acquire all these strategies to evade an effective immune response, which may eventually support the prolonged persistence of HPV infection and cervical cancer progression.
#61 Chapter 11: Human Papillomavirus | Pink Book | CDC
https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-11-human-papillomavirus.html?utm_source=chatgpt.com
HPV infection occurs at the basal epithelium. Although incidence of infection is high, most infections resolve spontaneously within a year or two. A small proportion of infected persons become persistently infected; persistent infection is the most important risk factor for the development of cervical cancer. […] High-risk or oncogenic HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers. High-risk types (including types 16, 18, and others) can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and anogenital cancers. High-risk HPV types are detected in 99% of cervical precancers. Type 16 is the cause of approximately 50% of cervical cancers worldwide, and types 16 and 18 together account for about 66% of cervical cancers. An additional five high-risk types, 31, 33, 45, 52, and 58, are responsible for another 15% of cervical cancers and 11% of all HPV-associated cancers. Infection with a high-risk HPV type is considered necessary for the development of cervical cancer but, by itself, is not sufficient to cause cancer. The vast majority of women with HPV infection, even those with high-risk HPV types, do not develop cancer.
#62 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
HPV infection is observed in >90% of cervical cancers. […] However, HPV is not the only virus participating in cervical cancer development; other hazardous situations such as coinfections (with herpes simplex virus type-2 and Chlamydia trachomatis), smoking, persistent use of oral contraceptives, multiparity, nutritional deficiencies, immunosuppression, and immune-associated diseases are also involved in cancer progression. […] Host immune responses fight against HPV infection and eliminate most of the viral part (nearly 90%) within 2â3 years or remain in the dormant phase, while the remaining 10% are converted into chronic infections; however, only 1% can cause cervical cancer. […] HPV can use the evasion process to escape the immune response. […] Therefore, HPV can multiply in host cells during viral replication without causing cytolysis, which neither stimulates the inflammatory process nor presents viral antigenic representatives.
#63 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
HPV infection is observed in >90% of cervical cancers. […] However, HPV is not the only virus participating in cervical cancer development; other hazardous situations such as coinfections (with herpes simplex virus type-2 and Chlamydia trachomatis), smoking, persistent use of oral contraceptives, multiparity, nutritional deficiencies, immunosuppression, and immune-associated diseases are also involved in cancer progression. […] Host immune responses fight against HPV infection and eliminate most of the viral part (nearly 90%) within 2â3 years or remain in the dormant phase, while the remaining 10% are converted into chronic infections; however, only 1% can cause cervical cancer. […] HPV can use the evasion process to escape the immune response. […] Therefore, HPV can multiply in host cells during viral replication without causing cytolysis, which neither stimulates the inflammatory process nor presents viral antigenic representatives.
#64 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
In host cells, type-I IFNs levels are reduced by the E6 and E7 proteins of HPV16 and generate an immune tolerance stage in the absence of costimulatory factors through inflammatory cytokines. […] Persistent HPV infection and a lower host immune response collectively support instigating carcinogenesis by conversion of a low-grade squamous intraepithelial lesion (LSIL) into a high-grade squamous intraepithelial lesion (HSIL), which ultimately transforms into an invasive form of cervical carcinoma. […] The involvement of HPV in cancer induction and progression can take many years for conversion into a carcinoma with the help of different tumor-stimulating steps, such as E6/E7 proteins that interact with cellular proteins. […] Additionally, a few reports have suggested that imbalanced immunity and chronic inflammation in the tumor microenvironment (TME) may provoke precancerous cervical lesions that turn into invasive cancer.
#65 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
In host cells, type-I IFNs levels are reduced by the E6 and E7 proteins of HPV16 and generate an immune tolerance stage in the absence of costimulatory factors through inflammatory cytokines. […] Persistent HPV infection and a lower host immune response collectively support instigating carcinogenesis by conversion of a low-grade squamous intraepithelial lesion (LSIL) into a high-grade squamous intraepithelial lesion (HSIL), which ultimately transforms into an invasive form of cervical carcinoma. […] The involvement of HPV in cancer induction and progression can take many years for conversion into a carcinoma with the help of different tumor-stimulating steps, such as E6/E7 proteins that interact with cellular proteins. […] Additionally, a few reports have suggested that imbalanced immunity and chronic inflammation in the tumor microenvironment (TME) may provoke precancerous cervical lesions that turn into invasive cancer.
#66 Natural history and pathogenesis of hpv | PPT
https://www.slideshare.net/slideshow/natural-history-and-pathogenesis-of-hpv/25975600
Persistent infection with high-risk HPV types is required for progression from normal cervical epithelium to pre-cancerous lesions and eventually invasive cervical cancer, with the contribution of additional genetic mutations and external cofactors over long periods of time. […] HPV types primarily target infections of the basal cells in the stratified squamous epithelium and metaplastic cells within squamocolumnar junctions. […] HPV mediated oncogenesis requires accumulation of additional genetic mutations over time. This suggests a long precancerous state in most cases of invasive cancer that allows the accumulation of secondary genetic mutations along with other cofactors such as smoking, carcinogens and hormonal. […] HPV infection plays an important role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer.
#67 Human papillomavirus infection – Wikipedia
https://en.wikipedia.org/wiki/Human_papillomavirus_infection
Human papillomavirus infection (HPV infection) is caused by a DNA virus from the Papillomaviridae family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and results in either warts or precancerous lesions. All warts are caused by HPV. These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat. Nearly all cervical cancer is due to HPV, and two strains HPV16 and HPV18 account for 70% of all cases. HPV16 is responsible for almost 90% of HPV-positive oropharyngeal cancers. Between 60% and 90% of the other cancers listed above are also linked to HPV. HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis. […] HPV is believed to cause cancer by integrating its genome into nuclear DNA. Some of the early genes expressed by HPV, such as E6 and E7, act as oncogenes that promote tumor growth and malignant transformation. HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number.
#68 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-024-02083-w
Persistent infection with hr-HPVs can cause precancerous lesions, thus evolving into various cancers, including head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC), anal cancer, as well as vulvar, penile, and vaginal cancers that are less prevalent. […] HPV triggers the DNA damage response (DDR) and employs the DDR mechanism to obtain materials necessary for viral DNA synthesis in the G2-like phase. […] Persistent hr-HPV infection can lead to the viral genome integrating with the host genome. Evidence has shown that the rate of genome integration is higher in HPV-16 and HPV-18 positive cancer samples than in non-cancer samples, and the integration facilitates intratumoral heterogeneity and clonal evolution. […] The predominant mechanism of integration is the microhomologies-mediated DNA repair pathway.
#69 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
The degradation of p53 by E6 is important because p53 is a transcription factor that regulates the expression of genes encoding regulators of cell cycle, DNA repair machinery, metabolism and apoptosis. […] Recent studies indicate the existence of an intricate HPV interactome, i.e., a network of intermolecular interactions of E6 and E7 with the host cell proteins. […] Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). […] The viral oncoproteins E6 and E7 are known to induce DNA damage, centrosome abnormalities and chromosomal segregation defects, thereby leading to chromosomal instability.
#70
https://journals.lww.com/md-journal/fulltext/2024/05240/molecular_mechanisms_of_human_papilloma_virus.6.aspx
Upon entry into the cell nucleus, HPV begins to exert integrative mechanisms to incorporate itself into cellular DNA. HPV RNA encoding the E6 and E7 oncogenes is initiated via the viral upstream regulatory region. The E6 oncoprotein will bind to p53 and disable its normal function for tumor suppression. This affects the host cell ability to undergo programmed cell death and growth arrest. This inactivation of p53 forces the host cell to enter the S phase of the cell cycle. The E7 oncoprotein will bind to the retinoblastoma protein, causing the release of the transcription factor E2F. The release of E2F activates cyclin-dependent kinases. Subsequent expression of the E1 and E2 oncogenes allows genomic instability at the integration locus. Persistence of the S phase of the cell cycle leads to uninhibited proliferation and differentiation of infected cells, eventually leading to dysplasia.
#71 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
The degradation of p53 by E6 is important because p53 is a transcription factor that regulates the expression of genes encoding regulators of cell cycle, DNA repair machinery, metabolism and apoptosis. […] Recent studies indicate the existence of an intricate HPV interactome, i.e., a network of intermolecular interactions of E6 and E7 with the host cell proteins. […] Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). […] The viral oncoproteins E6 and E7 are known to induce DNA damage, centrosome abnormalities and chromosomal segregation defects, thereby leading to chromosomal instability.
#72 HPV InfectionsâClassification, Pathogenesis, and Potential New Therapies
https://www.mdpi.com/1422-0067/25/14/7616
E7 binds to the retinoblastoma tumor suppressor protein pRb and to smaller proteins such as p107 and p130, inhibiting their action and, in the case of oncogenic HPV, leading to accelerated degradation. […] In most cases of HPV infection, the DNA remains in an episomal form, unintegrated into the host DNA, allowing the virus to replicate efficiently. […] The integration of the HPV genome into the cellular genome has been demonstrated to play a crucial role in the development of cancer. […] The E5 protein is responsible for the control of cell growth, differentiation, and immune modulation. […] The viral proteins act by increasing the expression of the catalytic subunit of telomerase, so-called human telomerase reverse transcriptase (hTERT). […] The association of E6 with PDZ may play roles in sustaining epithelial cell proliferation and the HPV replication cycle and also in tumor transformation. […] The effectiveness of treatment may be enhanced by the inclusion of methods which are based on the stimulation of the immune system in the fight against infection.
#73 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
High-risk E6 has the ability to activate the catalytic subunit of telomerase [hTERT (human telomerase reverse transcriptase)], which adds hexamer repeats to the telomeric ends of chromosomes. […] HPV16 E6 associates with E6AP, to promote the degradation of the transcriptional repressor NFX1-91, and consequently activate hTERT transcription; this repressor has also a role in HPV16 E6 activation of the oncogenic transcription factor NF-B. […] The activity of telomerase is normally restricted to the proliferative compartment of epithelium, and activation is associated with cellular immortalization and carcinogenesis. […] The silencing of E6 and E7 was found to decrease methylation of tumour suppressor genes and reverse the transformed phenotype of cervical cancer cells. […] The continuous activity of E6 and E7 proteins leads to aberrant cell proliferation, accumulation of oncogene mutations, and ultimately cervical cancer.
#74 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
Cervical carcinogenesis is a multistage process associated with the accumulation of DNA alterations in host cell genes. These alterations involve both epigenetic and genetic changes in oncogenes and tumour suppressor genes which are crucial regulators of cell cycle progression, chromosomal stability, telomere activation and apoptosis. But the pivotal step for the onset of tumorigenesis appears to be the integration of viral genome into the host. […] Integration of HPV DNA into the host cell genome is a key event in HPV-mediated carcinogenesis leading to aberrant proliferation and malignant progression. […] The early genes E6 and E7 play an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes p53 and pRb that regulate normal cellular proliferation.
#75 Human Papillomavirus (HPV) â Structure,epidemiology an…
https://otolaryngologypl.com/seo/article/01.3001.0003.2787/en?language=en
HPV infection plays an important role in carcinogenesis of the oropharynx tumors. The presence of viral genetic material in the tumor may influence prognosis and treatment method choices. […] Highly oncogenic HPV types: 16 and 18 induce precancerous lesions, increasing the risk of cancer development. The transition from dysplasia to invasive cancer appears to be associated with the integration of viral DNA into the genome of host cells. […] In case of an infection with HPV-types that have high oncogenic potential, integration of the viral DNA and the host’s chromosomes occurs.
#76 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
High-risk E6 has the ability to activate the catalytic subunit of telomerase [hTERT (human telomerase reverse transcriptase)], which adds hexamer repeats to the telomeric ends of chromosomes. […] HPV16 E6 associates with E6AP, to promote the degradation of the transcriptional repressor NFX1-91, and consequently activate hTERT transcription; this repressor has also a role in HPV16 E6 activation of the oncogenic transcription factor NF-B. […] The activity of telomerase is normally restricted to the proliferative compartment of epithelium, and activation is associated with cellular immortalization and carcinogenesis. […] The silencing of E6 and E7 was found to decrease methylation of tumour suppressor genes and reverse the transformed phenotype of cervical cancer cells. […] The continuous activity of E6 and E7 proteins leads to aberrant cell proliferation, accumulation of oncogene mutations, and ultimately cervical cancer.
#77 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-024-02083-w
Persistent infection with hr-HPVs can cause precancerous lesions, thus evolving into various cancers, including head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC), anal cancer, as well as vulvar, penile, and vaginal cancers that are less prevalent. […] HPV triggers the DNA damage response (DDR) and employs the DDR mechanism to obtain materials necessary for viral DNA synthesis in the G2-like phase. […] Persistent hr-HPV infection can lead to the viral genome integrating with the host genome. Evidence has shown that the rate of genome integration is higher in HPV-16 and HPV-18 positive cancer samples than in non-cancer samples, and the integration facilitates intratumoral heterogeneity and clonal evolution. […] The predominant mechanism of integration is the microhomologies-mediated DNA repair pathway.
#78 Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-024-02083-w
hr-HPV integration has numerous ways to alter the state of host cells, thereby promoting the initiation and development of cancers. […] The overexpression of E6 and E7 facilitates oncogenesis by disrupting the transcription of tumor suppressor genes and triggering flanking gene amplification. […] HPV integration contributes to the generation of extrachromosomal DNA (ecDNA), which enables cells to proliferate unlimitedly, making them promising drivers of clonal evolution. […] HPV integration induces chromosomal instability, rendering host cells more susceptible to cancers. […] E6 and E7 are recognized as main oncoproteins in the process of oncogenesis. They can disturb the cell cycle, affect cell proliferation, inhibit apoptosis, and alter cellular metabolism, leading to the occurrence and development of cancers.
#79 Non-sexual HPV transmission and role of vaccination for a better future (Review)
https://www.spandidos-publications.com/10.3892/etm.2020.9316
The process of cancer development from HPV infection takes ~5-10 years minimum and 20-25 years on average. […] Cervical carcinogenesis is represented by 4 causal stages: HPV acquisition; HPV persistence (vs. clearance); Progression to precancerous lesions; Invasive cancer. […] The route of HPV transmission is primarily through skin-to-skin or skin-to-mucosa contact. Sexual transmission is the most documented, but there have been studies suggesting non-sexual ways. […] The horizontal transmission of HPV includes fomites, fingers, and mouth, skin contact (other than sexual). […] Self-inoculation is described in studies as a potential HPV transmission route. […] Vertical transmission from mother to newborn is another HPV transmittal route. […] The possibility of vertical HPV infection was discussed as early as 1950, in a study on infantile anogenital warts, congenital conjunctival papilloma, and juvenile laryngeal papillomatosis.
#80 Natural history and pathogenesis of hpv | PPT
https://www.slideshare.net/slideshow/natural-history-and-pathogenesis-of-hpv/25975600
HPV is stealthy and evades the immune system. Natural infection with HPV does not reliably protect against future infection or reactivation. […] Only persistent high-risk infection of the cervical epithelium appears to trigger neoplastic progression. […] HPV type is the strongest factor affecting the risk of viral persistence. […] HPV 16 is highly carcinogenic with an absolute risk of CIN 3 approaching 40% at 3-5 years. […] The average time from HPV infection to CIN 3 is 7-15 years, peaking at 25-30 years. […] Transition into invasive cancer is influenced by high-risk HPV and the immature metaplastic epithelium of the transformation zone (TZ). […] HPV infection is very common and in most cases does not cause health problems, but some high-risk HPV types can cause cervical cancer over many years if left untreated. […] HPV works by integrating into the host cell’s genome and inactivating tumor suppressor proteins, leading to uncontrolled cell growth.
#81 Current understanding of the mechanism of HPV infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3493113/
HPVs (human papillomaviruses) and other papillomaviruses have a unique mechanism of infection that has likely evolved to limit infection to the basal cells of stratified epithelium, the only tissue in which they replicate. Recent studies in a mouse cervicovaginal challenge model indicate that, surprisingly, the virus cannot initially bind to keratinocytes in vivo. Rather it must first bind via its L1 major capsid protein to heparan sulfate proteoglycans (HSPGs) on segments of the basement membrane (BM) exposed after epithelial trauma and undergo a conformational change that exposes the N-terminus of L2 minor capsid protein to furin cleavage. L2 proteolysis exposes a previously occluded surface of L1 that binds an as yet undetermined cell surface receptor on keratinocytes that have migrated over the BM to close the wound. Papillomaviruses are the only viruses that are known to initiate their infectious process at an extracellular site.
#82 Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
https://pmc.ncbi.nlm.nih.gov/articles/PMC419925/
Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.
#83 Core Concepts – Human Papillomavirus Infection – Self-Study Lessons – National STD Curriculum
https://www.std.uw.edu/go/comprehensive-study/hpv
Human papillomavirus (HPV) is a small, non-enveloped, double-stranded DNA virus that has oncogenic potential. […] The HPV types that infect humans have a known specificity for mucosal and cutaneous epithelium. Infection with HPV occurs at the basal cell layer of stratified squamous epithelial cells. Infection stimulates cellular proliferation in the epithelium, and the infected cells display a broad spectrum of changes, with a spectrum of cellular outcomes that include inapparent infection, benign hyperplasia (papilloma), precancerous lesions, and invasive carcinoma. To effectively replicate, HPV must utilize the host cellular machinery. During the process, the viral protein product encoded by E6 binds to the p53 tumor suppressor gene product, which results in the premature degradation of the p53 protein. The E7 protein binds to a tumor suppressor proteinâthe retinoblastoma proteinâand inhibits its function. The E6 and E7 proteins mediate much of the HPV oncogenic potential by assisting the cell in evading host immunity, a process that facilitates virion production in differentiating epithelial cells.
#84 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
Cervical carcinogenesis is a multistage process associated with the accumulation of DNA alterations in host cell genes. These alterations involve both epigenetic and genetic changes in oncogenes and tumour suppressor genes which are crucial regulators of cell cycle progression, chromosomal stability, telomere activation and apoptosis. But the pivotal step for the onset of tumorigenesis appears to be the integration of viral genome into the host. […] Integration of HPV DNA into the host cell genome is a key event in HPV-mediated carcinogenesis leading to aberrant proliferation and malignant progression. […] The early genes E6 and E7 play an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes p53 and pRb that regulate normal cellular proliferation.
#85 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2
The degradation of p53 by E6 is important because p53 is a transcription factor that regulates the expression of genes encoding regulators of cell cycle, DNA repair machinery, metabolism and apoptosis. […] Recent studies indicate the existence of an intricate HPV interactome, i.e., a network of intermolecular interactions of E6 and E7 with the host cell proteins. […] Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). […] The viral oncoproteins E6 and E7 are known to induce DNA damage, centrosome abnormalities and chromosomal segregation defects, thereby leading to chromosomal instability.
#86 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis
https://www.mdpi.com/2076-0817/12/12/1380
The E7 protein can also directly interact with E2F1 in a retinoblastoma-independent manner in an in vitro and in vivo study, in which the E7 protein generated by the HR-HPVs binds more tightly to E2F1 than to LR-HPVs and activates E2F1-dependent transcription and promoter activities, which participate in the deregulation of the cell cycle and induction of transformation. […] HPV uses a variety of immune evasion mechanisms to suppress immune responses and promote cancer progression. […] HPV can show an immune escape strategy not only by hiding itself from recognition by immune cells by downregulating viral antigens, but also by disturbing the expression of immune response proteins, which further encourages prolonged viral persistence. […] HPV can acquire all these strategies to evade an effective immune response, which may eventually support the prolonged persistence of HPV infection and cervical cancer progression.
#87 Human Papillomavirus (HPV) Vaccines – NCI
https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet
HPV vaccines protect against infection with human papillomaviruses (HPV). HPV is a group of more than 200 related viruses, of which more than 40 are spread through direct sexual contact. Among these, two HPV types cause genital warts, and about a dozen HPV types can cause certain types of cancercervical, anal, oropharyngeal, penile, vulvar, and vaginal. […] Clinical trials have shown that HPV vaccines are highly effective in preventing cervical infection with the types of HPV they target when given before first exposure to the virusthat is, before individuals begin to engage in sexual activity. HPV vaccines have also been found to reduce infections in other tissues that HPV infects, including the anus and oral region. […] The current HPV vaccines are based on virus-like particles (VLPs) that are formed by HPV surface components. VLPs are not infectious because they lack the viruss DNA. However, they closely resemble the natural virus, and antibodies against the VLPs also have activity against the natural virus. The VLPs have been found to be strongly immunogenic, which means that they induce high levels of antibody production by the body. This makes the vaccines highly effective.
#88 Pathogenesis of HPV-transformed cells – ATB – Applied Tumor Biology, University Hospital Heidelberg
https://atb-heidelberg.de/projects/hpv-projects/hpvcancerpathogenesis/
One essential consequence of HPV oncogene signaling is the E7-triggered overexpression of the cell cycle regulator p16INK4a that is conveyed by epigenetic activity of the demethylase KDM6B. […] One particular focus of our research are the epigenetic modifications that occur during the course of an HPV infection and are in turn promoting the formation of cancer. […] Our research in HPV pathogenesis provides the foundation for our diagnostic and therapeutic projects.
#89 The pathogenesis of HPV within oropharyngeal cancer – Oracle Head and Neck Cancer UK
https://oraclehnc.org.uk/the-pathogenesis-of-hpv-within-oropharyngeal-cancer
It is not yet understood how HPV causes head and neck cancer (HNC). […] The team will describe the HPV lifecycle and characterise the disease within the tonsil to examine how infections lead to cancer, whether biomarkers can be identified which predict cancer, and whether infections are influenced by lifestyle.