Opryszczka narządów płciowych – Patofizjologia i mechanizm

Opryszczka narządów płciowych
Patofizjologia i mechanizm

Zakażenie wirusem opryszczki narządów płciowych (HSV-2, rzadziej HSV-1) dotyka około 520 milionów osób w wieku 15-49 lat globalnie (13%, dane z 2020 r.) i znacząco zwiększa ryzyko zakażenia HIV. HSV przenosi się przez kontakt bezpośredni z błonami śluzowymi lub uszkodzoną skórą, głównie drogą płciową, a wirus replikuje się w nabłonku narządów płciowych, następnie zasiedlając zwoje nerwowe (S2-S5). Po pierwotnej infekcji wirus wnika do neuronów czuciowych, gdzie utrzymuje się w stanie latencji, regulowanym epigenetycznie przez transkrypty LAT. Reaktywacja wirusa, wywołana czynnikami takimi jak stres czy uraz, prowadzi do nawrotów klinicznych lub bezobjawowego siewstwa, które jest głównym źródłem transmisji. Bezobjawowe siewstwo HSV-2 utrzymuje się nawet do 10 lat po zakażeniu, z wykrywalnym wirusem w około 17% dni. Terapia przeciwwirusowa (acyklowir, walacyklowir, famcyklowir) zmniejsza objawy i siewstwo o 70-80%, ale nie eliminuje wirusa.

Patogeneza zakażenia wirusem opryszczki narządów płciowych

Zakażenie wirusem opryszczki narządów płciowych, powodowane głównie przez wirus opryszczki pospolitej typu 2 (HSV-2), chociaż coraz częściej również przez wirus typu 1 (HSV-1), stanowi istotny problem zdrowotny na całym świecie. Szacuje się, że HSV-2 dotyka około 520 milionów (13%) osób w wieku 15-49 lat na całym świecie (dane z 2020 roku). Zakażenie HSV-2 zwiększa ryzyko zakażenia wirusem HIV około trzykrotnie, a osoby z podwójnym zakażeniem HIV i HSV-2 częściej przenoszą HIV na inne osoby.¹

Transmisja wirusa

Transmisja zakażenia HSV zależy od bliskiego, osobistego kontaktu osoby seronegatywnej z kimś wydzielającym wirusa. Wirus musi mieć kontakt z powierzchniami błon śluzowych lub uszkodzoną skórą, aby doszło do zakażenia.² Zakażenie HSV-2 jest zwykle konsekwencją transmisji przez kontakt płciowy. Wirus replikuje się w skórze narządów płciowych, okołogenitalnej lub okolicy odbytu, następnie dochodzi do zasiedlenia zwojów krzyżowych.³ Transmisja odbywa się poprzez bliski kontakt osobisty, a zakażenie następuje poprzez inokulację wirusa do podatnych powierzchni błon śluzowych (np. jamy ustnej, szyjki macicy, spojówki) lub przez małe pęknięcia w skórze. Wirus jest łatwo inaktywowany w temperaturze pokojowej i przez wysuszenie; stąd też rozprzestrzenianie się drogą aerozolową i przez przedmioty jest rzadkie.⁴

HSV-1 i HSV-2 mogą być przenoszone, choć rzadko, z zarażonych matek na noworodki podczas porodu i poprzez kontakt ustny z opiekunami po urodzeniu, prowadząc do opryszczki noworodków – choroby o wysokiej śmiertelności. Ryzyko przeniesienia na noworodka jest wyższe, gdy zakażenie seronegatywnej matki następuje w trzecim trymestrze ciąży.⁵⁶

Infekcja pierwotna i replikacja wirusa

Po wniknięciu do organizmu, zarówno HSV-1, jak i HSV-2 typowo uzyskują dostęp do organizmu poprzez błony śluzowe narządów płciowych lub jamy ustnej. Wirus następnie replikuje się w nabłonku wielowarstwowym płaskim, skąd jest pobierany przez rozgałęziające się niezmielinizowane włókna nerwowe czuciowe.⁷ Infekcje pierwotne zazwyczaj atakują nabłonek błon śluzowych, gdzie produkowane są liczne potomne wiriony i uwalniane przez lizę komórek.⁸

Wirus wnika do komórek nabłonkowych poprzez interakcję ze specyficznymi receptorami na powierzchni komórki za pomocą glikoprotein, które wystają z osłonki wirusowej. Po wniknięciu, w jądrze komórki gospodarza natychmiast rozpoczyna się replikacja wirusa. Najpierw transkrybowany jest gen wirusowy, co prowadzi do syntezy białek wirusowych, replikacji genomu wirusa i składania potomnych wirusów.⁹

Wirusowy liniowy DNA wnika do jądra przez por jądrowy. Komórkowa polimeraza RNA II i białka wirusowe transkrybują geny HSV. Ekspresja genów następuje w uporządkowanej kaskadzie podczas replikacji litycznej. Białko tegumentu VP16 tworzy kompleks z komórkowym czynnikiem 1 (HCF-1) i białkiem wiążącym oktamer-1 (Oct-1), który wiąże się z promotorem genów IE, kierując ich ekspresją.¹⁰

Latencja i reaktywacja

HSV posiada dwa unikalne biologiczne właściwości wpływające na patogenezę i następującą po niej chorobę u ludzi. Obydwa wirusy mają zdolność do inwazji i replikacji w ośrodkowym układzie nerwowym oraz zdolność do ustanowienia zakażenia latentnego w zwojach korzeni grzbietowych.¹¹ Po wniknięciu HSV-1 i HSV-2 zakażają zakończenia nerwowe i przemieszczają się transportem wstecznym do jąder neuronów czuciowych. Wirus namnaża się w niewielkiej liczbie neuronów czuciowych, które ostatecznie ulegają zniszczeniu. W zdecydowanej większości zakażonych neuronów genom wirusowy pozostaje przez całe życie człowieka w stanie episomalnym.¹²

Latencja jest interesującą funkcją przetrwania HSV-2, ponieważ genom wirusowy jest obecny w stanie niezakaźnym, z potencjałem do wywołania nawracającego zakażenia. Znaczącą rolę odgrywa regulacja epigenetyczna, latencja/” title=”transkrypt związany z latencją” class=”to-tag” data-termid=”69889″>transkrypty związane z latencją (LATs), czynniki odpowiedzialne za ustanowienie i odwrócenie latencji.¹³

Neurony czuciowe zawierające wirusa zawierają jądrowe transkrypty pochodzące z około 8,5 kbp sekwencji flankujących sekwencję UL. Transkrypty te znane są jako transkrypty związane z latencją lub LAT. Obfite RNA o wielkości 2,5 i 1,5 kbp nie odgrywają roli w ustanowieniu lub utrzymaniu stanu latentnego, chociaż mogą odgrywać rolę w reaktywacji.¹⁴

Reaktywacja występuje, gdy normalna ekspresja genów wirusowych wznawia się, z ponownym pojawieniem się wirusa na powierzchniach błon śluzowych.¹⁵ Białka wirusowe zaangażowane w kierowanie ekspresją genów wirusowych podczas replikacji litycznej, takie jak VP16, nie są ekspresjonowane podczas latencji.¹⁶

Mechanizmy molekularne zakażenia HSV

Struktura i genom wirusa

HSV to alfawirus z rodziny herpeswirusów. Jest to wirus osłonkowy o średnicy około 160 nm z liniowym, dwuniciowym genomem DNA. Ogólna homologia sekwencji między HSV-1 i HSV-2 wynosi około 50%. HSV-1 ma tropizm do nabłonka jamy ustnej, natomiast HSV-2 do nabłonka narządów płciowych. Zakażenie HSV jest zapośredniczone przez przyłączenie za pomocą wszechobecnych receptorów do komórek, w tym neuronów czuciowych, prowadząc do ustanowienia latencji.¹⁷

Wirusy HSV-1 i HSV-2 mają wielkość 150-200 nm i strukturalnie składają się z czterech głównych komponentów: DNA, nukleokapsydu, tegumentu i lipidowej osłonki. Genom HSV to pojedyncza, liniowa cząsteczka dwuniciowego DNA (około 152 000 par zasad kodujących co najmniej 74 geny); genom DNA jest zamknięty w kapsydzie ikozaedrycznym, nazywanym również nukleokapsydem lub rdzeniem wirusowym. Tegument, określany jako macierz, to amorficzna, bogata w białko warstwa otaczająca kapsyd. Osłonka stanowi najbardziej zewnętrzną część HSV i składa się z dwuwarstwy lipidowej błony najeżonej zestawem 12 różnych typów glikoprotein. Glikoproteiny są niezbędne do wniknięcia wirusa i wywołują przeciwciała neutralizujące. Różnice w glikoproteinie G (gG) między HSV-1 i HSV-2 zostały wykorzystane w rozwoju swoistych typowo testów serologicznych HSV.¹⁸

Cykl replikacyjny i mechanizmy molekularne

Cykl życiowy zarówno HSV-1, jak i HSV-2 obejmuje kilka kluczowych etapów. Kapsyd jest transportowany do jądra z pomocą dyneiny, dynaktyny i białka szoku cieplnego 90. W jądrze regulowana sekwencyjna ekspresja genów wirusowych, obejmująca geny natychmiastowo wczesne, wczesne i późne, prowadzi do syntezy różnych białek, w tym białek komórek zakażonych i białek tegumentu, które odgrywają kluczową rolę w replikacji wirusowej i tworzeniu komponentów wirusowych.¹⁹

Po wniknięciu do docelowej cytoplazmy, białka tegumentu wewnętrznego współpracują z aktynami i miozynami gospodarza, aby ułatwić wsteczny transport kapsydu wirusowego wzdłuż mikrotubul w kierunku poru jądrowego, gdzie genom wirusowy jest uwalniany do jądra poprzez przegrupowanie białek kapsydu.²⁰

Etap cyklu replikacyjnego	Kluczowe procesy molekularne	Zaangażowane białka/czynniki
Adsorpcja i wniknięcie	Przyłączenie do receptorów komórkowych, fuzja osłonki z błoną komórkową	Glikoproteiny wirusowe, receptory komórkowe
Transport do jądra	Wsteczny transport kapsydu wzdłuż mikrotubul	Dyneina, dynaktyna, białko szoku cieplnego 90
Ekspresja genów wirusowych	Kaskadowa ekspresja genów (natychmiastowo wczesne, wczesne, późne)	VP16, HCF-1, Oct-1, polimeraza RNA II
Replikacja DNA	Synteza wirusowego DNA	Wirusowe polimerazy i białka replikacyjne
Składanie i uwalnianie	Formowanie kapsydu, pakowanie DNA, pączkowanie	Białka strukturalne wirusa, enzymy komórkowe
Ustanowienie latencji	Inaktywacja ekspresji większości genów wirusowych	LAT, regulacja epigenetyczna
Reaktywacja	Wznowienie ekspresji genów wirusowych, replikacja i uwolnienie	Czynniki stresu, reorganizacja chromatyny

Transport neuronalny i ustanowienie latencji

Po pierwotnym zakażeniu i replikacji w miejscu ekspozycji, HSV przemieszcza się wzdłuż włókien nerwowych do zwojów czuciowych. Z wirusową replikacją w miejscu pierwotnego zakażenia, albo nienaruszony wirion, albo bardziej prawdopodobnie kapsyd jest transportowany wstecznie przez neurony do zwojów korzeni grzbietowych, gdzie po kolejnej rundzie replikacji wirusa, ustanawiana jest latencja.²¹

W przypadku zakażeń narządów płciowych HSV, zwoje korzenia krzyżowego (S2-S5) są zaangażowane w ustanawianie latencji. Reaktywacja i replikacja latentnego HSV, zawsze w obszarze zaopatrywanym przez zwoje, w których została ustanowiona latencja, może być indukowana przez różne bodźce (np. gorączka, uraz, stres emocjonalny, światło słoneczne, menstruacja), co prowadzi do jawnego lub ukrytego nawracającego zakażenia i wydzielania HSV.²²

Odpowiedź immunologiczna a patogeneza HSV

Mechanizmy obronne gospodarza

Cykl zakażenia HSV jest kontrolowany przez układ odpornościowy na kilku poziomach. Po wniknięciu do organizmu, wrodzone i adaptacyjne procesy odpornościowe regulują stopień replikacji, który ma miejsce w błonie śluzowej. To określa, ile wirusa uzyskuje dostęp do zwojów korzeni grzbietowych, staje się latentnym i następnie ulega reaktywacji.²³ Na poziomie zwojów korzeni grzbietowych, latencja i reaktywacja podlegają kontroli immunologicznej. Po przeniesieniu wirusa do zakończeń aksonalnych, poziom replikacji jest determinowany przez mechanizm adaptacyjnej odpowiedzi immunologicznej na styku z komórkami nabłonkowymi w błonie śluzowej.²⁴

Odporność komórkowa jest ważną obroną przeciwko opryszczce pospolitej. Rozsiew zakażenia opryszczką pospolitą może wystąpić u osób z upośledzonym funkcjonowaniem komórek T, takich jak biorcy przeszczepów narządów i osoby z AIDS.²⁵ Naturalne komórki zabójcze (NK) odgrywają znaczącą rolę we wczesnej obronie, rozpoznając i niszcząc komórki zakażone HSV.²⁶

Istnieją również mechanizmy śmierci komórkowej, które stanowią wewnątrzkomórkową obronę przeciwko zakażeniom wirusowym, ale wirusy utrudniają śmierć zakażonych komórek, co w przeciwnym razie ograniczyłoby zakażenie.²⁷

Strategie unikania odpowiedzi immunologicznej

HSV-2 jest dobrze wyposażony w czynniki zjadliwości, które modulują i unikają odpowiedzi immunologicznej.²⁸ Zdolność wirusa do unikania obrony wewnątrzkomórkowej i ustanawiania długotrwałej latencji w neuronach gospodarza jest kluczowym elementem jego patogenezy. Mechanizmy, które pozwalają wirusowi na przetrwanie i unikanie odpowiedzi immunologicznej, obejmują:

Zablokowanie prezentacji antygenów wirusowych na powierzchni komórek zakażonych²⁹
Hamowanie apoptozy w zakażonych neuronach, co umożliwia przetrwanie wirusa³⁰
Modulacja odpowiedzi interferonowej gospodarza³¹
Wpływ na system ubikwityna-proteasom gospodarza³²

Mechanizmy te pozwalają wirusowi HSV na ustanowienie długotrwałej latencji w neuronach gospodarza i okresowe reaktywacje, które prowadzą do objawowych lub bezobjawowych epizodów wysiewu wirusa.³³

Kliniczne aspekty zakażenia HSV narządów płciowych

Przebieg kliniczny i nawroty

Opryszczka narządów płciowych może wystąpić podczas zakażenia pierwotnego i reaktywacji, chociaż zakażenia pierwotne zwykle mają cięższy przebieg.³⁴ Im cięższe zakażenie pierwotne, tym większe prawdopodobieństwo wystąpienia nawrotów, co odzwierciedla się w rozmiarze, liczbie i zasięgu zmian.³⁵

Pierwotna opryszczka narządów płciowych charakteryzuje się tworzeniem się licznych, obustronnych, bolesnych i rozległych owrzodzeń narządów płciowych, które goją się bez pozostawiania blizn w ciągu 12 dni. U pacjentów występują również tkliwe powiększone węzły chłonne, gorączka, złe samopoczucie i bóle mięśniowe. Rzadko choroba może również powodować aseptyczne zapalenie opon mózgowych z sztywnością karku i silnym bólem głowy. Nawracająca opryszczka narządów płciowych trwa krócej, jest łagodniejsza i nie daje objawów ogólnoustrojowych. Głównym objawem choroby są prodromalne parestezje w kroczu, narządach płciowych lub pośladkach, a następnie tworzenie się zgrupowanych zmian w zewnętrznym obszarze narządów płciowych. Zmiany goją się bez blizn w ciągu 2-5 dni.³⁶

Bezobjawowe siewstwo wirusa

Badania wykazały, że większość osób z seropozytywnym wynikiem HSV-2 ma bezobjawowe siewstwo wirusa. Bezobjawowe siewstwo HSV u kobiet najczęściej występuje z sromu i okolicy okołoodbytniczej, podczas gdy u mężczyzn występuje ze skóry prącia i okolicy okołoodbytniczej. Bezobjawowe siewstwo wirusa jest krótsze niż siewstwo podczas nawrotów klinicznych, ale ilość wydzielanego wirusa jest podobna w epizodach objawowych i subklinicznych.³⁷

Odsetek dni z bezobjawowym siewstwem HSV-2 w narządach płciowych jest najwyższy w pierwszym roku po zakażeniu i stopniowo zmniejsza się wraz z upływem czasu, choć nawet po 10 latach od zakażenia siewstwo pozostaje stosunkowo częste, z wykrywalnym siewstwem w około 17% dni. Uważa się, że większość transmisji HSV-2 występuje z siewstwem wirusa podczas epizodów bezobjawowego siewstwa. Terapia przeciwwirusowa znacznie zmniejsza siewstwo HSV-2 o 70-80%, ale go nie eliminuje.³⁸

Terapia przeciwwirusowa

Nie istnieje lek, który może wyleczyć wirus opryszczki. Jednak lekarz może przepisać lek przeciwwirusowy, taki jak acyklowir, aby zapobiec namnażaniu się wirusa.³⁹ Dostępne metody leczenia HSV-2, w tym analogi nukleozydów takie jak acyklowir, walacyklowir i famcyklowir, zmniejszają objawy, ale nie eliminują wirusa.⁴⁰

Opryszczka narządów płciowych jest leczona lekami przeciwwirusowymi, takimi jak acyklowir, walacyklowir, famcyklowir i pencyklowir. Walacyklowir i famcyklowir są zatwierdzone do przewlekłej supresji opryszczki narządów płciowych. Profilaktyka doustnymi acyklowirem jest zalecana w celu zahamowania nawrotów opryszczki narządów płciowych pod koniec ciąży. Terapia supresyjna z walacyklowirem może być stosowana w celu zapobiegania częstym nawrotom opryszczki narządów płciowych.⁴¹

Aktualne badania nad wirusem HSV

Nowe strategie terapeutyczne

Obecne badania koncentrują się na opracowaniu nowych strategii zapobiegania i leczenia chorób wywołanych przez HSV.⁴² Obiecujące kierunki badań obejmują:

Rozwój szczepionek profilaktycznych i terapeutycznych przeciwko HSV⁴³
Badania nad mechanizmami prowadzącymi do latencji i reaktywacji⁴⁴
Nowe związki przeciwwirusowe ukierunkowane na specyficzne białka wirusa lub gospodarza⁴⁵
Strategie zakłócające mechanizm wyciszania w neuronach gospodarza⁴⁶

Jedna z potencjalnych strategii leczenia opryszczki polega na zakłóceniu mechanizmu wyciszania obecnego w neuronach gospodarza. Umożliwiłoby to namnażanie się wirusa, który mógłby być następnie zabity przez nowo zaprojektowane leki przeciwwirusowe.⁴⁷

Regulacja ekspresji genów i chromatyny

Nowe badania zidentyfikowały mechanizm, który odgrywa rolę w kontrolowaniu tego, jak wirus opryszczki przełącza się między uśpionym a aktywnym stadium zakażenia. Odkryto, że wirus przełącza się między stadium „latentnym” a stadium „litycznym”, w którym aktywnie się replikuje, w zależności od tego, jak ściśle jego DNA jest spakowane w wiązki zwane chromatyną.⁴⁸

Gdy wirus opryszczki wnika do komórki, komórka próbuje się chronić, owijając wirusowe DNA ściśle wokół białek podobnych do szpuli zwanych histonami i kondensując je w chromatynę, co powoduje, że wirus staje się uśpiony. Ale jeśli komórki nie mają powodzenia, chromatyna jest luźno związana, pozostawiając wirusowe DNA dostępne. Cząsteczki wirusa mogą wtedy włączyć swoje geny i replikować się za pomocą maszynerii komórkowej, aby rozpocząć zakażenie lityczne, powodując chorobę.⁴⁹

Przyszłe kierunki badań

Przyszłe badania prawdopodobnie skupią się na pełniejszym zrozumieniu mechanizmów ustanawiania latencji i reaktywacji HSV, co jest kluczowe dla opracowania skutecznych terapii.⁵⁰ Ponadto, badania nad interakcjami wirus-gospodarz i komórkowymi mechanizmami obronnymi mogą prowadzić do odkrycia nowych celów terapeutycznych.⁵¹

Obiecujące strategie zawierają szczepionki podjednostkowe i mRNA, które stanowią bramę do prezentacji układowi odpornościowemu złożonych składów antygenowych, potencjalnie w tym epitopów komórek T i B. Następne wyzwanie dotyczy samej technologii rozwoju szczepionek, w szczególności szczepionek mRNA i systemów dostarczania LNP.⁵²

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Materiały źródłowe

#1
https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus
Genital herpes caused by HSV-2 affects an estimated 520 million (13%) people aged 1549 years worldwide (2020 data). […] HSV-2 is much more likely than genital HSV-1 infection to cause recurrent symptoms. […] HSV-2 infection increases the risk of acquiring HIV infection by approximately three-fold. Additionally, people with both HIV and HSV-2 infection are more likely to spread HIV to others. […] In immunocompromised people, including those with advanced HIV infection, herpes can have more severe symptoms and more frequent recurrences. Rare complications of HSV-2 include meningoencephalitis (brain infection) and disseminated infection.
#2 Pathogenesis and disease – Human Herpesviruses – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK47449/
The transmission of herpes simplex virus (HSV) infection is dependent upon intimate, personal contact of a susceptible seronegative individual with someone excreting HSV. Virus must come in contact with mucosal surfaces or abraded skin for infection to be initiated. With viral replication at the site of primary infection, either an intact virion or, more simply, the capsid is transported retrograde by neurons to the dorsal root ganglia where, after another round of viral replication, latency is established. […] The more severe the primary infection, as reflected by the size, number, and extent of lesions, the more likely it is that recurrences will ensue. Although replication sometimes leads to disease and, infrequently, results in life-threatening infection (e.g., encephalitis), the host-virus interaction leading to latency predominates. After latency is established, a proper stimulus causes reactivation; virus becomes evident at mucocutaneous sites, appearing as skin vesicles or mucosal ulcers.
#3 Pathogenesis and disease – Human Herpesviruses – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK47449/
Infection with HSV-1 generally occurs in the oropharyngeal mucosa. The trigeminal ganglion becomes colonized and harbors latent virus. However, it has been increasingly common to detect evidence of HSV-1 in the genital tract, usually the consequence of oral-genital sex. When such occurs, recurrences of HSV-1 in the genital tract are uncommon. Acquisition of HSV-2 infection is usually the consequence of transmission by genital contact. Virus replicates in the genital, perigenital or anal skin sites with seeding of the sacral ganglia. […] Operative definitions of the nature of the infection are of pathogenic relevance. Susceptible individuals (namely, those without pre-existing HSV antibodies) develop primary infection after the first exposure to either HSV-1 or HSV-2. A recurrence of HSV is known as recurrent infection. Initial infection is when an individual with pre-existing antibodies to one type of HSV (namely, HSV-1 or HSV-2) can experience a first infection with the opposite virus type (namely, HSV-2 or HSV-1, respectively).
#4 Herpes Simplex: Background, Microbiology, Pathophysiology
https://emedicine.medscape.com/article/1132351-overview
Cellular immunity is an important defense against herpes simplex. Dissemination of herpes simplex infection can occur in people with impaired T-cell immunity, such as in organ transplant recipients and in individuals with AIDS. Herpes simplex infection can also complicate burn wounds or damaged skin such as in atopic dermatitis or other allergic dermatoses. […] HSV is transmitted by close personal contact, and infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the skin. The virus is readily inactivated at room temperature and by drying; hence, aerosol and fomitic spread are rare.
#5 Pathogenesis and virulence of herpes simplex virus
https://pmc.ncbi.nlm.nih.gov/articles/PMC8923070/
The percentage of HSV-specific T cells in blood of immunocompetent individuals after resolution of acute infection is low. […] The presence of HSV-specific CD8 T cells that could control HSV reactivation in mouse and human sensory ganglia does not match with the frequent reactivation observed in humans. […] The adaptive immune response is required to control latent HSV and to clear the virus upon reactivation. […] The presence of immune cells susceptible to HIV infection might contribute to HIV acquisition even in the presence of anti HSV therapy. […] The lack of a mature immune system in neonates probably contributes to the severity of HSV infection. […] The risk of transmission to the newborn is higher when infection of a seronegative mother occurs in the third trimester of pregnancy.
#6 Pathogenesis and virulence of herpes simplex virus
https://pmc.ncbi.nlm.nih.gov/articles/PMC8923070/
The disease is more common in women than men, at least in certain geographical locations. […] The adaptive immune response is very important to control HSV infection and reactivation. […] The presence of immune cells susceptible to HIV infection might contribute to HIV acquisition even in the presence of anti HSV therapy. […] The lack of a mature immune system in neonates probably contributes to the severity of HSV infection. […] The risk of transmission to the newborn is higher when infection of a seronegative mother occurs in the third trimester of pregnancy. […] The disease is more common in women than men, at least in certain geographical locations. […] The adaptive immune response is very important to control HSV infection and reactivation. […] The presence of immune cells susceptible to HIV infection might contribute to HIV acquisition even in the presence of anti HSV therapy.
#7 Azthena logo with the word Azthena
https://www.news-medical.net/health/Herpes-Simplex-Mechanism.aspx
Both HSV-1 and HSV-2 typically access the body through the genital or oral mucosa. From here, the virus then replicates in the stratified squamous epithelium, where it is then taken up by ramifying unmyelinated sensory nerve fibers. […] Next, HSV undergoes retrograde microtubule-associated transport to the neuronal cell bodies in the dorsal root ganglia (DRG) near the spinal cord, where acute infection is followed by lifelong latent infection. The virus remains in a dormant state within this collection of nerve cells. Periodically, the virus becomes reactivated and travels through anterograde microtubule-associated transport back into the stratified squamous epithelium of skin or mucosa, where replication occurs and the virus is shed into genital or oral secretions. […] The cycle of HSV infection is controlled by the immune system on several levels. Upon entering the body, innate and adaptive immune processes regulate the degree of replication that takes place in the mucosa. This determines how much of the virus accesses the DRG, becomes latent and then becomes reactivated.
#8
https://link.springer.com/article/10.1186/s43556-024-00199-7
Primary infections typically target the mucosal epithelium, where many progeny are produced and released through cell lysis. […] Host cell entry mainly involves two pathways: post-attachment fusion and endocytosis and phagocytosis-like uptake, both of which involve multiple viral glycoproteins. […] Blocking the virus at the entry step is a beneficial and broad strategy for developing vaccines and antiviral drugs, and several types of HSV substances targeting these targets have been developed, such as anti-HSPG peptides, anti-HSV antibodies, vaccines targeting glycoproteins, and inhibitors. […] After the viral capsid and tegument enter the target cytoplasm, inner tegument proteins collaborate with host actin and myosin to facilitate the retrograde transport of the viral capsid along microtubules towards the nuclear pore, where the viral genome is released into the nucleus through rearrangement of the capsid proteins.
#9 Herpes simplex virus(HSV): structure and genome, mode of transmission, pathogenesis, infection, laboratory diagnosis and treatment – Online Biology Notes
https://www.onlinebiologynotes.com/herpes-simplex-virushsv-structure-genome-mode-transmission-pathogenesis-infection-laboratory-diagnosis-treatment/
Virus enter through skin and mucus membrane and multiply locally […] Binding of glycoprotein trigger fusion of viral envelope with host cell membrane and this fusion causes the release of nucleo-capsid into cytoplasm and is transported to nucleus. […] In the nucleus of host cell, virus replication occur immediately. At first Viral gene will be transcribed leading to synthesis of virus protein, replication of virus genome and assembly of progeny viruses.
#10 Pathogenesis and virulence of herpes simplex virus
https://pmc.ncbi.nlm.nih.gov/articles/PMC8923070/
On the other hand, HSV is very well equipped with virulence factors that modulate and evade the immune response. […] Moreover, an excessive and uncontrolled response of the immune system can contribute to pathogenesis as observed in HSK. […] The viral linear DNA genome enters the nucleus through a nuclear pore. […] The cellular RNA polymerase II and viral proteins transcribe HSV genes. […] Gene expression follows an ordered cascade during lytic replication. […] The tegument protein VP16 forms a complex with host cell factor 1 (HCF-1) and octamer binding protein-1 (Oct-1) that binds to the promoter of IE genes, driving their expression. […] The reasons why HSV-1 and HSV-2 establish and maintain latency in neurons but not in other cell types are not completely clear. […] These results suggest that an efficient expression of IE genes is required to avoid establishment of latency.
#11 Pathogenesis and disease – Human Herpesviruses – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK47449/
Primary infection has, more recently, been labeled first-episode disease because some individuals present with what appears to be a clinically severe primary infection but have pre-existing antibodies to the causative type. This observation indicates that individuals may have a well-established latent infection before the first episode of clinically evident disease occurs. […] Reinfection with a different strain of HSV can occur, albeit extremely uncommon in the normal host and is called exogenous reinfection. […] HSV-1 and HSV-2 exhibit two unique biologic properties that influence pathogenesis and subsequent human disease. Both viruses have the capacity to invade and replicate in the CNS and the capacity to establish a latent infection in dorsal root ganglia. […] The term, neurovirulence, encompasses both neuroinvasiveness from peripheral sites and replication in neuronal cells.
#12 Pathogenesis and disease – Human Herpesviruses – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK47449/
Latency has been recognized biologically since the beginning of the century and has been extensively reviewed. Following entry, both HSV-1 and HSV-2 infect nerve endings and translocate by retrograde transport to the nuclei of sensory ganglia. The virus multiplies in a small number of sensory neurons, which are ultimately destroyed. In the vast majority of the infected neurons, the viral genome remains for the entire life of the individual in an episomal state. In a fraction of individuals, the virus reactivates and is moved by anterograde transport to a site at or near the portal of entry. Reactivations occur following a variety of local or systemic stimuli. […] Little is known regarding the mechanisms by which the virus establishes and maintains a latent state or is reactivated. There are in fact disagreements on the fate of neurons in which latent virus became reactivated.
#13 The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective
https://www.mdpi.com/1999-4915/15/11/2195
Latency is an interesting survival feature of HSV-2 as the viral genome is present in a non-infectious state with potential to cause recurrent infection. […] The role of epigenetic regulation, latency-associated transcripts (LATs), factors responsible for the establishment and reversal of latency, and drugs targeting the latent virus are some of the important aspects of HSV-2 latency. […] The cell-intrinsic immune response plays a crucial role in controlling HSV pathogenesis. However, viruses have developed mechanisms to evade intrinsic immunity, and data from previous studies suggest that HSV-2 latency in neurons and subsequent reactivation is a result of its ability to bypass immunity. […] Multiple host cell death pathways (apoptosis, necroptosis, pyroptosis, and autophagy) constitute the cell-intrinsic defense mechanisms against viral infections, but viruses hinder infected cell death that would otherwise limit the infection.
#14 Pathogenesis and disease – Human Herpesviruses – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK47449/
Sensory neurons harboring virus contain nuclear transcripts arising from approximately 8.5 kbp of the sequences flanking the UL sequence. These transcripts are known as the latency associated transcripts or LATs. […] The abundant 2.5 and 1.5 kbp RNA play no role in the establishment or maintenance of the latent state although they may play a role in reactivation. […] Usually, replication of HSV-1 and HSV-2 destroys the infected cell, but reactivation of latent virus may not destroy neurons harboring the virus. This suggestion is based on the observation that patients do not suffer from local anesthesia at the site of frequent, multiple recurrences.
#15 HERPES SIMPLEX VIRUSES | Harrison’s Manual of Medicine
https://harrisons.unboundmedicine.com/harrisons/view/Harrisons-Manual-of-Medicine/623260/all/HERPES_SIMPLEX_VIRUSES
The herpes simplex viruses HSV-1 and HSV-2 are linear, double-stranded DNA viruses that share 50% sequence homology. Exposure to HSV at mucosal surfaces or abraded skin sites permits viral entry and replication in cells of the epidermis and dermis prior to infection of neuronal cells and development of a latent infection in ganglia. […] Reactivation occurs when normal viral gene expression resumes, with reappearance of the virus on mucosal surfaces. […] Both antibody-mediated and cell-mediated immunity (including type-specific immunity) are clinically important.
#16 Pathogenesis and virulence of herpes simplex virus
https://pmc.ncbi.nlm.nih.gov/articles/PMC8923070/
The intrinsic and innate immune responses are key to protect against HSV-1 infection of the CNS and subsequent pathologies, including HSE. […] The role of the TLR3 signaling pathway seems specific for HSV-1, since children with these defects are not more susceptible to other viral infections. […] The suggested role of microglia in protection, based on mouse experiments, correlates with the presence of activated microglia in the proximity of HSV-1 infected cells in the temporal lobe of HSE patients. […] The viral proteins involved in driving viral gene expression during lytic replication, such as VP16, are not expressed during latency. […] The expression of chemokines and other chemoattractants by activated microglia induces infiltration of peripheral leukocytes. […] The expression of many of these proteins and thereby angiogenesis continues after virus clearance.
#17 Herpes Simplex: Background, Microbiology, Pathophysiology
https://emedicine.medscape.com/article/1132351-overview
Herpes simplex viruses are ubiquitous, host-adapted pathogens that cause a wide variety of disease states. Two types exist: herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Both are closely related but differ in epidemiology. HSV-1 is traditionally associated with orofacial disease, whereas HSV-2 is traditionally associated with genital disease. Lesion location, however, is not necessarily indicative of viral type, as HSV-1 is associated with genital infections more often than HSV-2 in some unique subpopulations. […] HSV belongs to the alpha herpesvirus group. It is an enveloped virus that is approximately 160 nm in diameter with a linear, double-stranded DNA genome. The overall sequence homology between HSV-1 and HSV-2 is about 50%. HSV-1 has tropism for oral epithelium, while HSV-2 has tropism for genital epithelium. HSV infection is mediated through attachment via ubiquitous receptors to cells, including sensory neurons, leading to establishment of latency.
#18 Core Concepts – Genital Herpes – Self-Study Lessons – National STD Curriculum
https://www.std.uw.edu/go/comprehensive-study/genital-herpes
Both HSV-1 and HSV-2 are 150 to 200 nm alpha-herpesviruses that are structurally comprised of four major components: DNA, nucleocapsid, tegument, and lipid envelope. The HSV genome is a single, linear molecule of double-stranded DNA (approximately 152,000 base pairs that encode at least 74 genes); the DNA genome is encased in an icosahedral capsid, also referred to as the nucleocapsid or viral core. The tegument, referred to as the matrix, is an amorphous protein-rich layer that surrounds the capsid. The envelope makes up the outermost part of HSV and consists of a lipid bilayer membrane studded with an array of 12 distinct types of glycoproteins. The glycoproteins are required for viral entry and elicit neutralizing antibodies. Differences in glycoprotein G (gG) between HSV-1 and HSV-2 have been utilized in the development of HSV type-specific serologic tests.
#19 The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective
https://www.mdpi.com/1999-4915/15/11/2195
As we delve deeper into understanding the intricate cellular interactions involved in HSV-2 pathogenesis, the potential for developing novel therapeutic approaches targeting cellular proteins and pathways offers hope for more effective management and treatment of this persistent global health concern. […] The life cycle of both HSV-1 and -2 comprises several pivotal stages, which have been comprehensively discussed in many reports. […] The capsid is then transported to the nucleus with the assistance of dynein, dynactin, and heat shock protein 90. […] Within the nucleus, the regulated sequential expression of viral genes, encompassing immediate early, early, and late genes, leads to the synthesis of various proteins, including infected cell proteins and tegument proteins, all of which play pivotal roles in viral replication and the formation of viral components.
#20
https://link.springer.com/article/10.1186/s43556-024-00199-7
Primary infections typically target the mucosal epithelium, where many progeny are produced and released through cell lysis. […] Host cell entry mainly involves two pathways: post-attachment fusion and endocytosis and phagocytosis-like uptake, both of which involve multiple viral glycoproteins. […] Blocking the virus at the entry step is a beneficial and broad strategy for developing vaccines and antiviral drugs, and several types of HSV substances targeting these targets have been developed, such as anti-HSPG peptides, anti-HSV antibodies, vaccines targeting glycoproteins, and inhibitors. […] After the viral capsid and tegument enter the target cytoplasm, inner tegument proteins collaborate with host actin and myosin to facilitate the retrograde transport of the viral capsid along microtubules towards the nuclear pore, where the viral genome is released into the nucleus through rearrangement of the capsid proteins.
#21 Pathogenesis and disease – Human Herpesviruses – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK47449/
The transmission of herpes simplex virus (HSV) infection is dependent upon intimate, personal contact of a susceptible seronegative individual with someone excreting HSV. Virus must come in contact with mucosal surfaces or abraded skin for infection to be initiated. With viral replication at the site of primary infection, either an intact virion or, more simply, the capsid is transported retrograde by neurons to the dorsal root ganglia where, after another round of viral replication, latency is established. […] The more severe the primary infection, as reflected by the size, number, and extent of lesions, the more likely it is that recurrences will ensue. Although replication sometimes leads to disease and, infrequently, results in life-threatening infection (e.g., encephalitis), the host-virus interaction leading to latency predominates. After latency is established, a proper stimulus causes reactivation; virus becomes evident at mucocutaneous sites, appearing as skin vesicles or mucosal ulcers.
#22 Herpes Simplex: Background, Microbiology, Pathophysiology
https://emedicine.medscape.com/article/1132351-overview
HSV-1 and HSV-2 are characterized by the following unique biological properties: Neurovirulence (the capacity to invade and replicate in the nervous system); Latency (the establishment and maintenance of latent infection in nerve cell ganglia proximal to the site of infection): In orofacial HSV infections, the trigeminal ganglia are most commonly involved, while, in genital HSV infection, the sacral nerve root ganglia (S2-S5) are involved; Reactivation: The reactivation and replication of latent HSV, always in the area supplied by the ganglia in which latency was established, can be induced by various stimuli (eg, fever, trauma, emotional stress, sunlight, menstruation), resulting in overt or covert recurrent infection and shedding of HSV. In immunocompetent persons who are at an equal risk of acquiring HSV-1 and HSV-2 both orally and genitally, HSV-1 reactivates more frequently in the oral rather than the genital region. On the other hand, HSV-2 reactivates 8-10 times more commonly in the genital region than in the orolabial regions. Reactivation is more common and severe in immunocompromised individuals.
#23 Azthena logo with the word Azthena
https://www.news-medical.net/health/Herpes-Simplex-Mechanism.aspx
Both HSV-1 and HSV-2 typically access the body through the genital or oral mucosa. From here, the virus then replicates in the stratified squamous epithelium, where it is then taken up by ramifying unmyelinated sensory nerve fibers. […] Next, HSV undergoes retrograde microtubule-associated transport to the neuronal cell bodies in the dorsal root ganglia (DRG) near the spinal cord, where acute infection is followed by lifelong latent infection. The virus remains in a dormant state within this collection of nerve cells. Periodically, the virus becomes reactivated and travels through anterograde microtubule-associated transport back into the stratified squamous epithelium of skin or mucosa, where replication occurs and the virus is shed into genital or oral secretions. […] The cycle of HSV infection is controlled by the immune system on several levels. Upon entering the body, innate and adaptive immune processes regulate the degree of replication that takes place in the mucosa. This determines how much of the virus accesses the DRG, becomes latent and then becomes reactivated.
#24 Azthena logo with the word Azthena
https://www.news-medical.net/health/Herpes-Simplex-Mechanism.aspx
At the DRG level, latency and reactivation is subject to immune control. After the virus has been transported to the axon terminals, the level of replication is determined by an adaptive immune mechanism at the interface with epithelial cells in the mucosa. This also determines whether clinical disease or asymptomatic shedding takes place.
#25 Herpes Simplex: Background, Microbiology, Pathophysiology
https://emedicine.medscape.com/article/1132351-overview
Cellular immunity is an important defense against herpes simplex. Dissemination of herpes simplex infection can occur in people with impaired T-cell immunity, such as in organ transplant recipients and in individuals with AIDS. Herpes simplex infection can also complicate burn wounds or damaged skin such as in atopic dermatitis or other allergic dermatoses. […] HSV is transmitted by close personal contact, and infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the skin. The virus is readily inactivated at room temperature and by drying; hence, aerosol and fomitic spread are rare.
#26 Herpes simplex virus 1 (HSV-1)- An Overview
https://microbenotes.com/herpes-simplex-virus-1-hsv-1/
HSV-1 infects epithelial cells and infection begins with the attachment of virus particles to susceptible cells. […] Virions interact with specific cell-surface receptors through glycoproteins that project from the viral envelope. […] The typical lesion produced by HSV is the vesicle, a ballooning degeneration of intra-epithelial cells, which contains infectious fluid. […] Natural killer (NK) cells play a significant role in early defenses by recognizing and destroying HSV-infected cells. […] HSV shows three unique biological properties: neurovirulence, latency, and reactivation. […] After the infection at the local site of inoculation virus then invades the local nerve ending; and is transported by retrograde axonal flow to the dorsal root ganglia, where it replicates further, and then undergoes latency.
#27 The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective
https://www.mdpi.com/1999-4915/15/11/2195
Latency is an interesting survival feature of HSV-2 as the viral genome is present in a non-infectious state with potential to cause recurrent infection. […] The role of epigenetic regulation, latency-associated transcripts (LATs), factors responsible for the establishment and reversal of latency, and drugs targeting the latent virus are some of the important aspects of HSV-2 latency. […] The cell-intrinsic immune response plays a crucial role in controlling HSV pathogenesis. However, viruses have developed mechanisms to evade intrinsic immunity, and data from previous studies suggest that HSV-2 latency in neurons and subsequent reactivation is a result of its ability to bypass immunity. […] Multiple host cell death pathways (apoptosis, necroptosis, pyroptosis, and autophagy) constitute the cell-intrinsic defense mechanisms against viral infections, but viruses hinder infected cell death that would otherwise limit the infection.
#28 Pathogenesis and virulence of herpes simplex virus
https://pmc.ncbi.nlm.nih.gov/articles/PMC8923070/
On the other hand, HSV is very well equipped with virulence factors that modulate and evade the immune response. […] Moreover, an excessive and uncontrolled response of the immune system can contribute to pathogenesis as observed in HSK. […] The viral linear DNA genome enters the nucleus through a nuclear pore. […] The cellular RNA polymerase II and viral proteins transcribe HSV genes. […] Gene expression follows an ordered cascade during lytic replication. […] The tegument protein VP16 forms a complex with host cell factor 1 (HCF-1) and octamer binding protein-1 (Oct-1) that binds to the promoter of IE genes, driving their expression. […] The reasons why HSV-1 and HSV-2 establish and maintain latency in neurons but not in other cell types are not completely clear. […] These results suggest that an efficient expression of IE genes is required to avoid establishment of latency.
#29 A dual inhibition mechanism of herpesviral ICP47 arresting a conformationally thermostable TAP complex | Scientific Reports
https://www.nature.com/articles/srep36907
As a centerpiece of antigen processing, the ATP-binding cassette transporter associated with antigen processing (TAP) became a main target for viral immune evasion. The herpesviral ICP47 inhibits TAP function, thereby suppressing an adaptive immune response. […] Binding of the active domain of ICP47 arrests TAP in an open inward facing conformation rendering the complex inaccessible for other viral factors. Based on our findings, we propose a dual interaction mechanism for ICP47. A per se destabilizing active domain inhibits the function of TAP, whereas a conserved C-terminal region additionally stabilizes the transporter. […] We demonstrate that the C-terminal extended region of ICP47 is necessary for complete stabilization of the TAP complex, whereas the N-terminal active domain is sufficient for TAP inhibition.
#30
https://link.springer.com/article/10.1186/s43556-024-00199-7
Overall, these results suggest that LAT helps establish and maintain HSV’s long-term latent infection in the host by preventing neuronal apoptosis and suppressing host immune responses. […] The complexity of the HSV immune escape mechanism may alter the host immune response, possibly triggering inflammation and other complications. […] The promise lies in subunit and mRNA vaccines, which provide a gateway to present the immune system with complex antigenic compositions, potentially including T cell and B cell epitopes. […] The next challenge concerns the vaccine development technology itself, particularly mRNA vaccines and LNP delivery systems. […] In summary, developing an effective vaccine and overcoming the limitations in its applications is a daunting task, and further research is urgently needed to comprehensively and deeply understand HSV.
#31 What Is the Herpes Simplex Virus? – Consensus: AI Search Engine for Research
https://consensus.app/home/blog/what-is-the-herpes-simplex-virus/
Herpes simplex virus remains a significant public health concern due to its widespread prevalence and potential for severe disease. Advances in understanding its molecular biology, pathogenesis, and immune evasion strategies are crucial for developing effective treatments and vaccines. […] Substantial advances in the past 50 years have enhanced our understanding of HSVs molecular biology, pathogenesis, and management. […] The virus has developed mechanisms to evade the immune system, contributing to its pathogenesis. Genetic polymorphisms in humans can also influence the severity of HSV infections. […] After primary infection, HSV establishes latency in sensory neurons. During latency, the virus remains dormant with limited gene expression. Reactivation can occur due to various stressors, leading to the production of new viral particles and potential disease recurrence.
#32 Antiviral mechanism of carvacrol on HSV-2 infectivity through inhibition of RIP3-mediated programmed cell necrosis pathway and ubiquitin-proteasome system in BSC-1 cells | BMC Infectious Diseases | Full Text
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05556-9
Carvacrol exhibits significant antiviral activity by inhibiting the HSV-2 proliferation process and HSV-2-induced TNF- increasing levels, decreasing RIP3 and MLKL protein expressions through the intracellular RIP3-mediated programmed cell necrosis pathway. […] Carvacrol also may exhibit anti-HSV-2 activity by reversing the ubiquitination decrease level caused by HSV-2 infection on the ubiquitin-proteasome system, which provides insights into the molecular mechanism. […] HSV-2 infection may cause the death of infected cell through RIP3-mediated programmed cell necrosis pathway, but this kind of death had nothing to do with autophagy, apoptosis, and pyroptosis. […] When carvacrol was applied on infected cells, it may exhibit anti-HSV-2 activity by inhibiting HSV-2-induced TNF- increased levels, decreasing RIP3 protein activity and weakening MLKL protein expression.
#33 Genital herpes guide: Risk factors and clinical manifestations – Canada.ca
https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/herpes-simplex-virus/risk-factors-clinical-manifestation.html
HSV transmission occurs via skin-to-skin contact during periods of symptomatic and asymptomatic viral shedding. […] After initial exposure, HSV enters the mucocutaneous tissues and replicates. After the initial replication, HSV enters a latent phase in sensory ganglia where it may remain dormant for years. Episodic reactivation may cause asymptomatic or symptomatic episodes of viral shedding. […] A recurrence is a clinically evident episode which is due to viral reactivation in sensory ganglia. […] Recurrences are clinically evident episodes which are due to viral reactivation in sacral sensory ganglia.
#34 Pathogenesis and virulence of herpes simplex virus
https://pmc.ncbi.nlm.nih.gov/articles/PMC8923070/
The chronic inflammatory response due to high level of proinflammatory cytokines and leukocyte infiltration can lead to corneal scarring, neovascularization and corneal nerve loss. […] The presence of immune cells susceptible to HIV infection might contribute to HIV acquisition even in the presence of anti HSV therapy. […] The lack of a mature immune system in neonates probably contributes to the severity of HSV infection. […] The risk of transmission to the newborn is higher when infection of a seronegative mother occurs in the third trimester of pregnancy. […] The disease is more common in women than men, at least in certain geographical locations. […] Genital herpes can occur during primary infection and reactivation, although primary infections tend to be more severe. […] The adaptive immune response is very important to control HSV infection and reactivation.
#35 Pathogenesis and disease – Human Herpesviruses – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK47449/
The transmission of herpes simplex virus (HSV) infection is dependent upon intimate, personal contact of a susceptible seronegative individual with someone excreting HSV. Virus must come in contact with mucosal surfaces or abraded skin for infection to be initiated. With viral replication at the site of primary infection, either an intact virion or, more simply, the capsid is transported retrograde by neurons to the dorsal root ganglia where, after another round of viral replication, latency is established. […] The more severe the primary infection, as reflected by the size, number, and extent of lesions, the more likely it is that recurrences will ensue. Although replication sometimes leads to disease and, infrequently, results in life-threatening infection (e.g., encephalitis), the host-virus interaction leading to latency predominates. After latency is established, a proper stimulus causes reactivation; virus becomes evident at mucocutaneous sites, appearing as skin vesicles or mucosal ulcers.
#36 Pathogen Safety Data Sheets: Infectious Substances â Herpes simplex virus – Canada.ca
https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/herpes-simplex-virus.html
Genital herpes: It is a sexually transmitted disease. Genital herpes is caused mainly by HSV-2, although HSV-1 has become as common as HSV-2 in primary genital infections in developed countries. Primary genital herpes is characterized by formation of multiple, bilateral, painful, and extensive genital ulcers, which heal without scarring within 12 days. Patients also present with tender enlarged lymph nodes, fever, malaise, and myalgia. Rarely, the disease may also cause aseptic meningitis with neck rigidity and severe headache. Recurrent genital herpes disease is of shorter duration, is milder and does not have systemic symptoms. The main manifestation of the disease is prodromal paresthesias in the perineum, genitalia or buttocks, followed by formation of grouped lesions on the external genital area. The lesions heal without scarring in 2-5 days.
#37 Core Concepts – Genital Herpes – Self-Study Lessons – National STD Curriculum
https://www.std.uw.edu/go/comprehensive-study/genital-herpes
Studies of HSV-2 seropositive persons have documented that most have asymptomatic viral shedding. Asymptomatic shedding of HSV in women most often occurs from the vulva and perianal area, whereas in men, it occurs from the penile skin and perianal area. Asymptomatic viral shedding is shorter than shedding during clinical recurrences, but the quantity of virus shed is similar in symptomatic and subclinical episodes. The percentage of days with asymptomatic HSV-2 genital shedding is highest in the first year after infection and gradually decreases over time, though even after 10 years of infection, the shedding remains relatively frequent, with shedding detected on about 17% of days. Most HSV-2 transmission is thought to occur with viral shedding during asymptomatic shedding episodes. Antiviral suppressive therapy dramatically reduces HSV-2 shedding by 70 to 80%, but it does not eradicate it. Genital HSV-1 shedding is less frequent than HSV-2 shedding, with shedding detected by culture on 2% of days. Following first-episode HSV-1, shedding is common but decreases significantly over a 1-year period. Shedding following first-episode HSV-1 is higher in persons with primary HSV-1 infection (absent HSV antibody at baseline) compared to those with nonprimary HSV-1 infection.
#38 Core Concepts – Genital Herpes – Self-Study Lessons – National STD Curriculum
https://www.std.uw.edu/go/comprehensive-study/genital-herpes
Studies of HSV-2 seropositive persons have documented that most have asymptomatic viral shedding. Asymptomatic shedding of HSV in women most often occurs from the vulva and perianal area, whereas in men, it occurs from the penile skin and perianal area. Asymptomatic viral shedding is shorter than shedding during clinical recurrences, but the quantity of virus shed is similar in symptomatic and subclinical episodes. The percentage of days with asymptomatic HSV-2 genital shedding is highest in the first year after infection and gradually decreases over time, though even after 10 years of infection, the shedding remains relatively frequent, with shedding detected on about 17% of days. Most HSV-2 transmission is thought to occur with viral shedding during asymptomatic shedding episodes. Antiviral suppressive therapy dramatically reduces HSV-2 shedding by 70 to 80%, but it does not eradicate it. Genital HSV-1 shedding is less frequent than HSV-2 shedding, with shedding detected by culture on 2% of days. Following first-episode HSV-1, shedding is common but decreases significantly over a 1-year period. Shedding following first-episode HSV-1 is higher in persons with primary HSV-1 infection (absent HSV antibody at baseline) compared to those with nonprimary HSV-1 infection.
#39 Herpes: Symptoms, causes, and treatment
https://www.medicalnewstoday.com/articles/151739
Herpes results from contracting the herpes simplex virus (HSV). It causes sores or blisters in or around the mouth or genitals, alongside other symptoms. There is currently no cure, but treatment can help manage symptoms. […] It typically develops due to HSV-2, although it can also develop due to HSV-1. […] According to the World Health Organization (WHO), HSV-1 typically spreads via oral contact, and HSV-2 typically spreads via sexual contact. […] When HSV is present on the skin, it can easily pass from person to person through contact with the moist skin of the mouth and genitals, including the anus. The virus may also spread through contact to the eyes and to other areas of the skin. […] No drug can cure the herpes virus. However, a doctor may prescribe an antiviral medication, such as acyclovir, to prevent the virus from multiplying. […] According to the U.K.s NHS, if a person uses antiviral medication, symptoms may resolve 1 to 2 days more quickly than if they had used no treatment.
#40 The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective
https://www.mdpi.com/1999-4915/15/11/2195
Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular processes, from harnessing host machinery for replication to subverting antiviral defenses like autophagy and programmed cell death, exemplifies the intricate interplay at the heart of its pathogenesis. […] HSV-2 possesses a double-stranded DNA genome with 74 genes encoding approximately 84 proteins, critical for viral component formation, infection, replication, and latency establishment. Infection, neuro-invasion, and latency establishment are HSV-2âs key features. […] The initial infection leads to viral replication at the exposure site and dormancy in the sacral ganglia, evading host immune responses in multiple ways. […] The available treatments for HSV-2, including nucleoside analogs like acyclovir, valacyclovir, and famciclovir, reduce symptoms but fail to eliminate the virus.
#41 Pathogen Safety Data Sheets: Infectious Substances â Herpes simplex virus – Canada.ca
https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/herpes-simplex-virus.html
Mode of transmission: Direct contact with infected secretions or mucous membranes/skin with lesions from an asymptomatic or symptomatic patients shedding the virus, is the main mode of transmission of HSV. Genital herpes is transmitted sexually. […] First aid/treatment: Genital herpes: Treated with antiviral drugs such as acyclovir, valacyclovir, famciclovir, and penciclovir. Valacyclovir, famciclovir are approved for chronic suppression of genital herpes. […] Prophylaxis: Prophylaxis with oral acyclovir is recommended to suppress genital HSV recurrences near the end of pregnancy. Suppressive therapy with Valcyclovir may be used to prevent frequent recurrences of genital herpes.
#42 Research on the Pathogenesis of Herpetic Diseases and Novel Treatment Strategies | Frontiers Research Topic
https://www.frontiersin.org/research-topics/59547/research-on-the-pathogenesis-of-herpetic-diseases-and-novel-treatment-strategiesundefined
Hence, it is important to study the virus-host interaction as well as viral pathogenesis, with the aim of developing novel strategies for the prevention and treatment of herpetic diseases. […] This Research Topic aims to provide a comprehensive and advanced publication platform for studies concerning the pathogenesis, the pathogenic viral factors, and key molecular events that mediate herpetic disease progression, as well as the novel treatment strategies of herpetic diseases. […] Specifically, perspectives focusing on the pathogenic mechanisms of herpes virus as well as the strategies for antiviral agents against herpes virus, including but not limited to the following, are highly welcome: 1) The pathogenic mechanism that mediates herpetic disease progression 2) The infection mechanisms for herpes virus including virus endocytosis, fusion, and transmission 3) The mechanisms of viral-host interaction including immune evasion and latent infection 4) The development of novel vaccines for herpes virus infection 5) The antiviral mechanisms of novel agents for herpetic diseases 6) The recent advances in the pharmacodynamics and clinical applications of anti-HSV agents.
#43
https://link.springer.com/article/10.1186/s43556-024-00199-7
Overall, these results suggest that LAT helps establish and maintain HSV’s long-term latent infection in the host by preventing neuronal apoptosis and suppressing host immune responses. […] The complexity of the HSV immune escape mechanism may alter the host immune response, possibly triggering inflammation and other complications. […] The promise lies in subunit and mRNA vaccines, which provide a gateway to present the immune system with complex antigenic compositions, potentially including T cell and B cell epitopes. […] The next challenge concerns the vaccine development technology itself, particularly mRNA vaccines and LNP delivery systems. […] In summary, developing an effective vaccine and overcoming the limitations in its applications is a daunting task, and further research is urgently needed to comprehensively and deeply understand HSV.
#44 Discovery reveals mechanism that turns herpes virus on and off | Cornell Chronicle
https://news.cornell.edu/stories/2019/11/discovery-reveals-mechanism-turns-herpes-virus-and
Latency and reactivation are a major focus for herpes virus research. […] When the herpes virus enters a cell, the cell tries to protect itself by wrapping the viral DNA tightly around spool-like proteins called histones and condensing it into chromatin, which causes the virus to go dormant. […] But if the cells are unsuccessful, the chromatin is only loosely bundled, leaving the viral DNA accessible. […] The virus particles can then turn on their genes and replicate using the cells machinery to start a lytic infection, causing disease. […] In the new study, however, the group showed that the dynamics of the chromatin regulate whether the entire herpes virus genome is turned on, which must occur before any individual genes can be expressed. […] This new mechanism represents a previously overlooked way to regulate gene expression at the level of the entire viral chromosome. […] The discovery opens up new directions for exploring how the virus reactivates after lying dormant. […] Herpes ability to lay low has thwarted efforts to create effective vaccines or antiviral drugs that fully prevent or cure the infection.
#45 A novel approach utilizing spirocyclic thiopyrimidinone compounds against herpes simplex virus with underlying antiviral mechanisms of action | Virology Journal | Full Text
https://virologyj.biomedcentral.com/articles/10.1186/s12985-025-02707-9
In recent decades, viral outbreaks have significantly threatened global health, with herpes simplex virus type 2 (HSV-2) being one of the most prevalent infections. This study evaluated novel spiropyrimidine derivatives as potential antiviral agents against HSV-2 […] The drug mechanism of infection studies indicated that compound 3 primarily inhibits HSV-2 at the viral adsorption stage, achieving approximately 83% inhibition and reducing viral multiplication by 34%. […] The evaluation of antiviral activity revealed that compounds 2, 3, and 5c were the most promising new inhibitors of human herpes simplex virus type-2 (HSV-2) among all the tested compounds, which serve as antiviral models for DNA virus inhibition. […] Considering how the antiviral drugs affect HSV-2, compound 3 resulted in 83% viral inhibition by adsorption, 34% by replication, and only 8% by viricidal mechanisms when the host cells were compared with the normal control cells, indicating that adsorption is the major mechanism of viral inhibition for compound 3.
#46 Feature: Tricking the herpes virus out of âhidingâ
http://arrafunding.uchicago.edu/news/feature_roizman.shtml
In neurons, the herpes virus allows itself to be silenced by its hosts defenses and lies dormant until it is activated by hormones or stress on the neurons. […] While the virus is dormant it is not vulnerable to antiviral drugs, but when the virus is fighting its hosts cellular defenses it is vulnerable. […] The primary health threat posed by the herpes virus occurs when it is reactivated from its dormant state and causes both new lesions in the person who harbors the virus and in others with whom the host comes into contact. […] One approach that might cure herpes, however, is to disrupt the silencing mechanism harbored in the hosts neurons. This would allow the virus to multiply, at which point the virus could be killed by newly designed antiviral drugs. […] To achieve this, Roizman and his colleagues need to know the mechanism by which the virus is silenced in neurons.
#47 Feature: Tricking the herpes virus out of âhidingâ
http://arrafunding.uchicago.edu/news/feature_roizman.shtml
In neurons, the herpes virus allows itself to be silenced by its hosts defenses and lies dormant until it is activated by hormones or stress on the neurons. […] While the virus is dormant it is not vulnerable to antiviral drugs, but when the virus is fighting its hosts cellular defenses it is vulnerable. […] The primary health threat posed by the herpes virus occurs when it is reactivated from its dormant state and causes both new lesions in the person who harbors the virus and in others with whom the host comes into contact. […] One approach that might cure herpes, however, is to disrupt the silencing mechanism harbored in the hosts neurons. This would allow the virus to multiply, at which point the virus could be killed by newly designed antiviral drugs. […] To achieve this, Roizman and his colleagues need to know the mechanism by which the virus is silenced in neurons.
#48 Discovery reveals mechanism that turns herpes virus on and off | ScienceDaily
https://www.sciencedaily.com/releases/2019/11/191114161905.htm
New research has identified a new mechanism that plays a role in controlling how the herpes virus alternates between dormant and active stages of infection. […] In Schang’s group, Mi Yao Hu and Esteban Flores Cortes discovered that the virus switches between the „latent” stage and the „lytic” stage, in which it is actively replicating, depending on how tightly its DNA is packaged into bundles called chromatin. […] When the herpes virus enters a cell, the cell tries to protect itself by wrapping the viral DNA tightly around spool-like proteins called histones and condensing it into chromatin, which causes the virus to go dormant. But if the cells are unsuccessful, the chromatin is only loosely bundled, leaving the viral DNA accessible. The virus particles can then turn on their genes and replicate using the cell’s machinery to start a lytic infection, causing disease.
#49 Discovery reveals mechanism that turns herpes virus on and off | ScienceDaily
https://www.sciencedaily.com/releases/2019/11/191114161905.htm
New research has identified a new mechanism that plays a role in controlling how the herpes virus alternates between dormant and active stages of infection. […] In Schang’s group, Mi Yao Hu and Esteban Flores Cortes discovered that the virus switches between the „latent” stage and the „lytic” stage, in which it is actively replicating, depending on how tightly its DNA is packaged into bundles called chromatin. […] When the herpes virus enters a cell, the cell tries to protect itself by wrapping the viral DNA tightly around spool-like proteins called histones and condensing it into chromatin, which causes the virus to go dormant. But if the cells are unsuccessful, the chromatin is only loosely bundled, leaving the viral DNA accessible. The virus particles can then turn on their genes and replicate using the cell’s machinery to start a lytic infection, causing disease.
#50 Discovery reveals mechanism that turns herpes virus on and off | Cornell University College of Veterinary Medicine
https://www.vet.cornell.edu/about-us/news/20191114/discovery-reveals-mechanism-turns-herpes-virus-and
With this new knowledge, researchers can further explore the interplay between the virus and host cells that determines whether viral DNA is expressed. […] Latency and gene regulation is a big problem because we do not know nearly enough about it, said Schang. […] The discovery opens up new directions for exploring how the virus reactivates after lying dormant.
#51
https://grantome.com/grant/NIH/R01-AI148478-02
Requirements for HSV-induced membrane fusion include the coordinated activities of four HSV glycoproteins (gD, the hererodimeric gHgL complex, and gB) and specific cellular receptors. […] Our central hypothesis is that gD, present in the viral envelope or on an infected cell surface, binds to a cellular receptor, such as nectin-1, on an uninfected cell and activates gHgL and gB via protein-protein interactions, resulting in fusion mediated by gB. […] The results of these studies will lead to an understanding of the mechanism of herpesvirus-induced membrane fusion and to new approaches for the prevention and treatment of herpesvirus infections.
#52
https://link.springer.com/article/10.1186/s43556-024-00199-7
Overall, these results suggest that LAT helps establish and maintain HSV’s long-term latent infection in the host by preventing neuronal apoptosis and suppressing host immune responses. […] The complexity of the HSV immune escape mechanism may alter the host immune response, possibly triggering inflammation and other complications. […] The promise lies in subunit and mRNA vaccines, which provide a gateway to present the immune system with complex antigenic compositions, potentially including T cell and B cell epitopes. […] The next challenge concerns the vaccine development technology itself, particularly mRNA vaccines and LNP delivery systems. […] In summary, developing an effective vaccine and overcoming the limitations in its applications is a daunting task, and further research is urgently needed to comprehensively and deeply understand HSV.