Wirus hiv i aids – Patofizjologia i mechanizm

Wirus hiv i aids
Patofizjologia i mechanizm

HIV, jako retrowirus z rodziny Lentivirus, infekuje komórki układu odpornościowego wyrażające receptor CD4 oraz koreceptory chemokinowe CCR5 lub CXCR4, prowadząc do progresywnej deplecji limfocytów T CD4+ poprzez mechanizmy bezpośrednie (lizę komórek zakażonych) oraz pośrednie, takie jak apoptoza, pyroptoza i efekt bystander. Tropizm wirusa (R5, X4, R5X4) determinuje przebieg zakażenia, gdzie szczepy R5 dominują we wczesnych fazach, a X4 pojawiają się w późniejszych etapach, wiążąc się z szybszą progresją do AIDS. Kluczową rolę w patogenezie odgrywa tkanka limfatyczna związana z błonami śluzowymi (GALT), gdzie dochodzi do masywnej utraty limfocytów CD4+ CCR5+ i uszkodzenia bariery jelitowej, co skutkuje translokacją mikroorganizmów i przewlekłą aktywacją immunologiczną. HIV tworzy rezerwuary latentne w makrofagach, spoczynkowych limfocytach T CD4+ oraz tkance limfatycznej, co utrudnia eliminację wirusa mimo terapii antyretrowirusowej (ART). Przewlekła aktywacja układu odpornościowego, spowodowana m.in. translokacją bakterii i stymulacją antygenową, prowadzi do dalszej deplecji limfocytów i immunosupresji.

Mechanizm patogenezy wirusa HIV i AIDS

Wirus hiv i aids (Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome) jest złożonym patogenem, którego działanie prowadzi do postępującego niszczenia układu odpornościowego. Zrozumienie mechanizmów patogenezy HIV jest kluczowe dla opracowania skutecznych strategii zapobiegania i leczenia zakażenia.¹² HIV jest retrowirusem należącym do rodzaju Lentivirus, który infekuje kluczowe komórki układu odpornościowego, prowadząc do ich postępującej destrukcji i ostatecznie upośledzenia odporności komórkowej.¹²

Struktura i charakterystyka wirusa HIV

HIV jest wirusem osłonkowym, diploidalnym, jednoniciowym RNA o dodatniej polarności, z pośrednim stadium DNA, które integruje się z genomem gospodarza jako prowirus i utrzymuje się w DNA komórki gospodarza.¹ Genom wirusa jest transkrybowany za pomocą enzymu odwrotnej transkryptazy, która przekształca wirusowe RNA w DNA, co stanowi kluczowy etap cyklu replikacyjnego.¹ Odwrotna transkryptaza jest podatna na błędy podczas konwersji RNA HIV do DNA, co prowadzi do licznych mutacji i zwiększa szansę wytworzenia szczepów odpornych na układ odpornościowy gospodarza oraz leki antyretrowirusowe.¹

Wejście wirusa do komórki i cykl replikacyjny

HIV infekuje komórki posiadające receptor CD4, głównie limfocyty T pomocnicze CD4+, monocyty/makrofagi oraz komórki dendrytyczne.¹² Proces wnikania wirusa do komórki jest wieloetapowy i wymaga obecności zarówno receptora CD4, jak i koreceptorów chemokinowych – najczęściej CCR5 lub CXCR4.¹ Białko osłonkowe wirusa gp120 wiąże się z receptorem CD4, co wywołuje zmiany konformacyjne umożliwiające interakcję z koreceptorem.¹²

Po związaniu się z koreceptorem, następują kolejne zmiany konformacyjne odsłaniające peptyd fuzyjny gp41, który wnika do błony komórkowej gospodarza, prowadząc do fuzji osłonki wirusowej z błoną komórkową i uwolnienia zawartości kapsydu do cytoplazmy.¹² Po wniknięciu do komórki, enzym odwrotna transkryptaza przepisuje jednoniciowy RNA wirusa na DNA, które następnie jest transportowane do jądra komórkowego i integrowane z DNA gospodarza przy udziale enzymu integrazy.¹

Zintegrowane prowirusowe DNA może pozostawać w stanie latentnym lub ulec transkrypcji, prowadząc do produkcji nowych wirionów. Transkrypcja wirusowego DNA wymaga obecności czynników transkrypcyjnych komórki gospodarza, szczególnie czynnika NF-κB, który jest aktywowany w aktywowanych limfocytach T.¹² Nowopowstałe białka wirusowe są składane w wiriony na wewnętrznej powierzchni błony komórkowej i uwalniane przez pączkowanie z powierzchni komórki.¹

Tropizm komórkowy i koreceptory

Szczepy HIV można sklasyfikować na podstawie ich tropizmu komórkowego i wykorzystywanych koreceptorów:¹

Szczepy M-tropowe (R5) – wykorzystują koreceptor CCR5 i infekują monocyty, makrofagi oraz limfocyty T, ale nie linie komórek T, które ekspresjonują głównie CXCR4¹
Szczepy T-tropowe (X4) – wykorzystują koreceptor CXCR4 i infekują linie komórek T oraz limfocyty T, ale nie makrofagi¹
Szczepy dual-tropowe (R5X4) – mogą wykorzystywać zarówno CCR5, jak i CXCR4 do infekowania różnych typów komórek¹

Kluczową rolę w przebiegu zakażenia HIV odgrywa tropizm wirusowy. Szczepy R5 dominują we wczesnych stadiach zakażenia i utrzymują się również w zaawansowanym stadium choroby.¹² Natomiast szczepy X4 pojawiają się zwykle w późniejszych etapach zakażenia u około 40% zakażonych osób i związane są z szybszą progresją do AIDS.¹

Niszczenie komórek CD4+ i progresja choroby

Charakterystyczną cechą patogenezy HIV jest postępująca utrata limfocytów CD4+. Mechanizmy prowadzące do deplecji tych komórek są złożone i obejmują zarówno bezpośrednie, jak i pośrednie procesy.¹²

Mechanizmy niszczenia limfocytów CD4+

Spadek liczby limfocytów CD4+ w przebiegu zakażenia HIV wynika z kilku nakładających się procesów:¹

Bezpośrednie zabijanie zakażonych komórek – HIV replikuje się w aktywowanych limfocytach T CD4+, prowadząc do ich lizy¹
Zabijanie komórek przez cytotoksyczne limfocyty T – CD8+ rozpoznają i eliminują zakażone komórki¹
Apoptoza – zaprogramowana śmierć komórkowa zakażonych i niezakażonych komórek¹²
Efekt bystander – niszczenie niezakażonych komórek CD4+ przez mechanizmy immunologiczne¹
Pyroptoza – specyficzna forma śmierci komórkowej nieproduktywnie zakażonych komórek CD4+, prowadząca do nasilonego stanu zapalnego¹

Dodatkowo, HIV wywołuje zaburzenia funkcji grasicy, co prowadzi do upośledzenia odtwarzania puli limfocytów T, przyczyniając się do postępującej deplecji limfocytów CD4+.¹

Rola przewlekłej aktywacji układu odpornościowego

Przewlekła aktywacja układu odpornościowego jest charakterystyczną cechą zakażenia HIV i stanowi kluczowy mechanizm prowadzący do postępującej immunosupresji.¹² Ciągła replikacja HIV prowadzi do stanu uogólnionej aktywacji immunologicznej, która utrzymuje się przez całą fazę przewlekłą zakażenia.¹

Aktywacja immunologiczna przyczynia się do deplecji limfocytów CD4+ poprzez:¹

Zwiększoną podatność aktywowanych limfocytów T na apoptozę¹
Skrócenie czasu przeżycia limfocytów T CD4+ i CD8+¹
Zaburzenia migracji limfocytów T¹
Wyczerpanie klonalne limfocytów T¹
Zubożenie puli pamięciowych limfocytów T¹

Mechanizmy leżące u podłoża przewlekłej aktywacji immunologicznej obejmują bezpośrednią stymulację przez białka wirusowe, przewlekłą stymulację antygenową oraz translokację bakterii i produktów bakteryjnych z jelita do krążenia na skutek uszkodzenia bariery jelitowej.¹

Fazy zakażenia HIV

Zakażenie HIV przebiega w kilku wyróżniających się fazach:¹

Faza ostra – charakteryzuje się wysokim poziomem wiremii, gwałtownym spadkiem liczby krążących limfocytów CD4+ oraz masową deplecją tych komórek w tkance limfatycznej związanej z błonami śluzowymi (GALT)¹²
Faza przewlekła – okres względnej równowagi między replikacją wirusa a odpowiedzią immunologiczną, z powolnym spadkiem liczby limfocytów CD4+¹
Faza AIDS – charakteryzuje się głębokim niedoborem odporności komórkowej (liczba limfocytów CD4+ spada poniżej 200 komórek/mm³) i zwiększoną podatnością na zakażenia oportunistyczne oraz nowotwory¹²

Rola tkanek limfatycznych i rezerwuarów wirusa

Tkanka limfatyczna związana z błonami śluzowymi (GALT) oraz inne tkanki limfatyczne odgrywają kluczową rolę w patogenezie HIV.¹²

Znaczenie tkanki limfatycznej związanej z błonami śluzowymi (GALT)

GALT stanowi główne miejsce replikacji HIV oraz destrukcji limfocytów CD4+, niezależnie od drogi zakażenia.¹ W ostrym zakażeniu HIV dochodzi do masywnej deplecji limfocytów CD4+ CCR5+ w GALT, co prowadzi do poważnych zaburzeń funkcjonowania układu odpornościowego związanego z błonami śluzowymi.¹

Uszkodzenie bariery jelitowej na skutek deplecji limfocytów CD4+ i komórek Th17 w błonie śluzowej jelita prowadzi do zwiększonej przepuszczalności ściany jelita („leaky gut”) i translokacji mikroorganizmów oraz ich produktów do krążenia, co nasila przewlekłą aktywację immunologiczną.¹²

Rezerwuary wirusa i latencja

HIV tworzy rezerwuary w różnych tkankach organizmu, co stanowi główną przeszkodę w eliminacji zakażenia.¹ Rezerwuary te obejmują:

Makrofagi – stanowią główne rezerwuary HIV w tkankach, mogą być obecne w mózgu, płucach, węzłach chłonnych, skórze, szpiku kostnym i krwi¹
Spoczynkowe limfocyty T CD4+ – zawierają latentne prowirusa, które mogą być reaktywowane¹
Tkanka limfatyczna związana z jelitem (GALT) – miejsce wczesnego zasiedlenia i tworzenia rezerwuaru prowirusa¹
Ośrodkowy układ nerwowy – HIV może infekować komórki mikrogleju i makrofagi w OUN¹

Mechanizm latencji polega na integracji prowirusa HIV z genomem komórki gospodarza bez aktywnej produkcji nowych wirionów.¹ Latentnie zakażone komórki nie wykazują ekspresji białek wirusowych, dzięki czemu unikają rozpoznania przez układ odpornościowy.¹

Rola makrofagów w patogenezie HIV

Makrofagi stanowią ważny cel dla HIV i odgrywają istotną rolę w patogenezie zakażenia.¹

Makrofagi jako cel i rezerwuar HIV

Makrofagi ekspresjonują receptor CD4 oraz koreceptory CCR5 i CXCR4, co czyni je podatnymi na zakażenie HIV.¹ W przeciwieństwie do limfocytów T CD4+, zakażone makrofagi nie ulegają efektowi cytopatycznemu wywołanemu przez wirusa, dzięki czemu mogą przetrwać przez długi czas jako rezerwuar wirusa.¹

Zakażone makrofagi są często obserwowane jako komórki wielojądrowe (syncytia) w OUN i innych tkankach zakażonych HIV, co świadczy o fuzji zakażonych komórek.¹ Makrofagi mogą również przenosić wirusa do innych komórek poprzez specyficzne synapsy wirusologiczne.¹

Rola makrofagów w rozprzestrzenianiu zakażenia

Makrofagi odgrywają istotną rolę w rozprzestrzenianiu zakażenia HIV w organizmie:¹

Służą jako nośniki dla rozprzestrzeniania wirusa między różnymi tkankami¹
Zakażone makrofagi w węzłach chłonnych produkują duże ilości cząstek wirusowych¹
Stanowią długotrwały rezerwuar wirusa, umożliwiający przetrwanie zakażenia mimo stosowania terapii antyretrowirusowej¹
Uczestniczą w przekazywaniu wirusa do niezakażonych limfocytów T CD4+¹

Mechanizmy immunopatogenne i wzajemne oddziaływania wirusa z układem odpornościowym

HIV wykorzystuje złożone mechanizmy do modulowania odpowiedzi immunologicznej gospodarza, co przyczynia się do przetrwania wirusa i progresji choroby.¹

Zaburzenia odpowiedzi immunologicznej

Zakażenie HIV prowadzi do licznych zaburzeń funkcji układu odpornościowego:¹

Zaburzenia produkcji przeciwciał – HIV wpływa na funkcje limfocytów B, prowadząc do wczesnego przełączania klas immunoglobulin w poliklonalnych limfocytach B, masywnej apoptozy limfocytów B i utraty ośrodków rozmnażania w tkance limfatycznej¹
Zmniejszona odpowiedź cytotoksycznych limfocytów T – wirus upośledza funkcje limfocytów T CD8+¹
Zaburzenia produkcji cytokin – zakażenie HIV prowadzi do zmiany profilu cytokin, w tym przesunięcia równowagi z odpowiedzi Th1 na Th2¹
Zaburzenia sygnalizacji komórkowej – HIV wpływa na sygnalizację receptora TCR i aktywację limfocytów T¹

Mechanizmy unikania odpowiedzi immunologicznej

HIV wykształcił liczne strategie umożliwiające uniknięcie rozpoznania i eliminacji przez układ odpornościowy:¹

Wysoka zmienność genetyczna – wysoka częstość mutacji spowodowana błędami odwrotnej transkryptazy umożliwia szybką ewolucję wariantów wirusowych¹²
Modulacja ekspresji cząsteczek powierzchniowych komórki gospodarza – białko Nef wirusa HIV obniża ekspresję CD4, MHC-I/II oraz innych molekuł immunologicznych na powierzchni zakażonych komórek¹²
Tworzenie rezerwuarów latentnych – HIV może utrzymywać się w stanie latentnym, unikając rozpoznania przez układ odpornościowy¹
Modulacja synaps immunologicznych – HIV zakłóca kontakty między limfocytami T a komórkami prezentującymi antygen, co modyfikuje odpowiedź limfocytów T¹

Rola białka Nef w patogenezie HIV

Białko Nef jest jednym z kluczowych czynników wirulencji HIV, odgrywającym istotną rolę w progresji zakażenia do AIDS:¹

Obniża ekspresję powierzchniową CD4, MHC-I/II i innych molekuł immunologicznych¹
Zakłóca dynamikę aktyny związaną z transportem pęcherzykowym i ruchem komórek¹
Moduluje sygnalizację aktywacji limfocytów T¹
Aktywuje czynniki transkrypcyjne NF-κB, AP1 i NFAT, promując transkrypcję wirusa¹
Blokuje transport wewnątrzkomórkowy cząsteczek niezbędnych do tworzenia synaps immunologicznych¹

Uszkodzenie narządów i układów w przebiegu zakażenia HIV

Zakażenie HIV prowadzi do uszkodzenia wielu narządów i układów, co wynika zarówno z bezpośredniego działania wirusa, jak i z mechanizmów immunopatologicznych.¹²

Uszkodzenie układu nerwowego

HIV może wnikać do ośrodkowego układu nerwowego (OUN) wkrótce po zakażeniu, prawdopodobnie poprzez zakażone monocyty i limfocyty, które przekraczają barierę krew-mózg.¹ W OUN HIV zakaża głównie komórki mikrogleju i makrofagi, ale może również pośrednio uszkadzać neurony poprzez:¹

Działanie neurotoksycznych białek wirusowych (gp120, tat)¹
Neurotoksyny wydzielane w odpowiedzi immunologicznej¹
Aktywację mikrogleju i stan zapalny¹

Zakażenie HIV może prowadzić do HIV-zależnych zaburzeń neurokognitywnych (HAND), które występują u ponad 50% nieleczonych pacjentów.¹ Encefalopatia HIV charakteryzuje się gliozą, ogniskami mikrogleju, okołonaczyniowym nagromadzeniem makrofagów i obecnością wielojądrzastych komórek olbrzymich.¹

Zaburzenia układu sercowo-naczyniowego, wątroby, nerek i innych narządów

HIV może bezpośrednio uszkadzać różne narządy i układy, prowadząc do:¹

Kardiomiopatii – bezpośrednie uszkodzenie mięśnia sercowego przez wirusa¹
Nefropatii – HIV może bezpośrednio infekować komórki nerkowe¹²
Uszkodzenia wątroby – zwiększone ryzyko chorób wątroby u osób żyjących z HIV¹
Zaburzeń endokrynologicznych – dysfunkcja osi hormonalnych i nieprawidłowe poziomy hormonów¹
Osteoporozy – zwiększone ryzyko chorób kości¹

Pomimo skutecznego leczenia antyretrowirusowego, osoby zakażone HIV mają zwiększone ryzyko rozwoju chorób sercowo-naczyniowych, kostnych, wątroby, nerek i układu nerwowego.¹

Zakażenia oportunistyczne i nowotwory związane z HIV

Postępujące uszkodzenie układu odpornościowego w przebiegu zakażenia HIV prowadzi do zwiększonej podatności na zakażenia oportunistyczne i nowotwory.¹

Zakażenia oportunistyczne

Zakażenia oportunistyczne pojawiają się gdy liczba limfocytów CD4+ spada poniżej określonych wartości progowych i stanowią główną przyczynę chorobowości i śmiertelności związanej z AIDS.¹ Najczęstsze zakażenia oportunistyczne obejmują:

Pneumocystis jirovecii (dawniej Pneumocystis carinii) – powodujący zapalenie płuc¹
Candida albicans – wywołujący kandydozę jamy ustnej i przełyku¹
Cytomegalowirus – powodujący zapalenie siatkówki, jelita i inne zakażenia¹
Herpes zoster – powodujący półpasiec¹
Patogeny jelitowe – takie jak Cryptosporidium, Giardia i Isospora belli¹
Mycobacterium tuberculosis – zakażenie gruźlicą jest częste u osób zakażonych HIV, szczególnie w regionach o wysokiej endemiczności gruźlicy¹

Nowotwory związane z zakażeniem HIV

Osoby zakażone HIV mają zwiększone ryzyko rozwoju nowotworów.¹ Nowotwory definiujące AIDS obejmują:

Mięsak Kaposiego – związany z zakażeniem ludzkim wirusem opryszczki typu 8 (HHV-8)¹
Chłoniaki nieziarnicze (NHL) – w tym chłoniak pierwotny ośrodkowego układu nerwowego¹
Inwazyjny rak szyjki macicy – związany z zakażeniem wirusem brodawczaka ludzkiego (HPV)¹

W erze skutecznej terapii antyretrowirusowej spektrum nowotworów u pacjentów zakażonych HIV uległo zmianie. Częstość występowania mięsaka Kaposiego i chłoniaków nieziarniczych znacznie się zmniejszyła, ale wzrósł względny udział nowotworów niedefiniujących AIDS (NADC), które obecnie stanowią istotny czynnik przyczyniający się do śmiertelności u osób żyjących z HIV.¹²

Wpływ terapii antyretrowirusowej na patogenezę HIV

Terapia antyretrowirusowa (ART) zmieniła naturalny przebieg zakażenia HIV, prowadząc do supresji replikacji wirusa, umożliwiając odbudowę układu odpornościowego i zapobiegając progresji do AIDS.¹²

Mechanizmy działania leków antyretrowirusowych

Leki antyretrowirusowe działają na różnych etapach cyklu replikacyjnego HIV:¹

Inhibitory wejścia – blokują wiązanie HIV do receptorów komórkowych lub fuzję wirusa z komórką
Inhibitory odwrotnej transkryptazy – blokują przepisanie RNA wirusa na DNA
Inhibitory integrazy – blokują integrację wirusowego DNA z genomem komórki gospodarza
Inhibitory proteazy – blokują dojrzewanie nowych wirionów

Odbudowa układu odpornościowego pod wpływem ART

Skuteczna terapia antyretrowirusowa prowadzi do:¹

Supresji replikacji wirusa, często do poziomu niewykrywalnego w standardowych testach¹
Wzrostu liczby limfocytów CD4+, co umożliwia częściową odbudowę układu odpornościowego¹
Zmniejszenia aktywacji immunologicznej¹
Zmniejszenia ryzyka rozwoju zakażeń oportunistycznych i nowotworów definiujących AIDS¹

Jednak odpowiedź na leczenie w różnych przedziałach anatomicznych jest nierównomierna. Odbudowa limfocytów CD4+ w GALT jest opóźniona i niepełna w porównaniu z krwią obwodową.¹ Ponadto, pomimo skutecznej terapii antyretrowirusowej, przewlekły stan zapalny i aktywacja immunologiczna mogą się utrzymywać, przyczyniając się do rozwoju chorób niezwiązanych z AIDS.¹

Ograniczenia terapii antyretrowirusowej

Pomimo skuteczności terapii antyretrowirusowej w supresji replikacji HIV, nie jest ona w stanie wyeliminować rezerwuarów wirusa, co uniemożliwia całkowite wyleczenie zakażenia.¹ Gówne ograniczenia ART obejmują:

Brak możliwości eliminacji latentnych rezerwuarów wirusa¹
Niepełna odbudowa układu odpornościowego, szczególnie w GALT¹
Utrzymujący się przewlekły stan zapalny i aktywacja immunologiczna¹
Konieczność dożywotniej terapii¹
Potencjalna toksyczność leków i interakcje lekowe¹

Trwają intensywne badania nad nowymi strategiami leczenia, które mogłyby prowadzić do funkcjonalnego wyleczenia zakażenia HIV poprzez eliminację rezerwuarów wirusa.¹²

Podsumowanie kluczowych aspektów patogenezy HIV

Patogeneza zakażenia HIV jest złożonym procesem, obejmującym wiele wzajemnie powiązanych mechanizmów:¹

HIV jest retrowirusem, który infekuje i niszczy limfocyty CD4+, makrofagi i komórki dendrytyczne, prowadząc do postępującego uszkodzenia układu odpornościowego¹
Wirus wykorzystuje receptor CD4 oraz koreceptory chemokinowe (CCR5 lub CXCR4) do wniknięcia do komórek¹
Deplecja limfocytów CD4+ wynika zarówno z bezpośredniego działania wirusa, jak i z mechanizmów pośrednich, w tym apoptozy, pyroptozy i aktywacji immunologicznej¹
Przewlekła aktywacja układu odpornościowego jest kluczowym mechanizmem prowadzącym do progresji choroby¹
HIV tworzy rezerwuary w różnych tkankach organizmu, co umożliwia przetrwanie wirusa mimo stosowania terapii antyretrowirusowej¹
Terapia antyretrowirusowa prowadzi do supresji replikacji wirusa i częściowej odbudowy układu odpornościowego, ale nie eliminuje rezerwuarów wirusa¹

Zrozumienie złożonych mechanizmów patogenezy HIV jest kluczowe dla opracowania nowych strategii terapeutycznych, w tym skutecznej szczepionki oraz metod prowadzących do funkcjonalnego wyleczenia zakażenia.¹²

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Materiały źródłowe

#1 Pathogenesis of HIV Infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3892619/
Over the past three decades of intense research on the contribution of viral and host factors determining the variability in HIV-1 infection outcome, HIV pathogenesis is still a fascinating topic that requires further study. […] An understanding of the exact mechanism of how these factors influencing HIV pathogenesis is critical to the development of effective strategies to prevent infection. […] Significant progress has been made in identifying the role of CCR5 (R5) and CXCR4 (X4) HIV strains in disease progression, particularly with the persistence of R5 HIV-1 strains at the AIDS stage. […] This indicates that R5 strains are as fit as X4 in causing CD4+ T cell depletion and in contribution to disease outcome, and so questions the prerequisite of the shift from R5 to X4 for disease progression.
#1 HIV – Wikipedia
https://en.wikipedia.org/wiki/HIV
The human immunodeficiency viruses (HIV) are two species of Lentivirus (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. […] HIV infects vital cells in the human immune system, such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including pyroptosis of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8+ cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.
#1 HIV Infection and AIDS: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/211316-overview
HIV produces cellular immune deficiency characterized by the depletion of helper T lymphocytes (CD4 cells). The loss of CD4 cells results in the development of opportunistic infections and neoplastic processes. […] HIV-1 and HIV-2 are retroviruses in the Retroviridae family, Lentivirus genus. They are enveloped, diploid, single-stranded, positive-sense RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA. […] The specific details of the disease process that leads to AIDS are not fully understood despite considerable progress in the virology of HIV and the immunology of the human host, much of which has been driven by the urge to better understand AIDS. […] There is a specific decline in the CD4 helper T cells, resulting in inversion of the normal CD4/CD8 T-cell ratio and dysregulation of B-cell antibody production.
#1 Human Immunodeficiency Virus (HIV) Infection – Infectious Diseases – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/infectious-diseases/human-immunodeficiency-virus-hiv/human-immunodeficiency-virus-hiv-infection
HIV infection destroys CD4+ lymphocytes and impairs cell-mediated immunity, increasing risk of certain infections and cancers. […] HIV can directly damage the brain, gonads, kidneys, and heart, causing cognitive impairment, hypogonadism, renal insufficiency, or cardiomyopathy. […] HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors. After attachment, HIV RNA and several HIV-encoded enzymes are released into the host cell. […] Viral replication requires that reverse transcriptase (an RNA-dependent DNA polymerase) copy HIV RNA, producing proviral DNA; this copying mechanism is prone to errors, resulting in frequent mutations and, thus, new HIV genotypes. […] Proviral DNA enters the host cells nucleus and is integrated into the host DNA in a process that involves integrase, another HIV enzyme.
#1 Human Immunodeficiency Virus (HIV) Infection – Infections – MSD Manual Consumer Version
https://www.msdmanuals.com/home/infections/human-immunodeficiency-virus-hiv-infection/human-immunodeficiency-virus-hiv-infection
HIV is a retrovirus. That is, it stores its genetic information as ribonucleic acid (RNA). Once inside a CD4+ lymphocyte, the virus uses an enzyme called reverse transcriptase to make a copy of its RNA, but the copy is made as deoxyribonucleic acid (DNA). HIV mutates easily at this point because reverse transcriptase is prone to making errors during the conversion of HIV RNA to DNA. These mutations make HIV more difficult to control because the many mutations increase the chance of producing HIV that can resist attacks by the persons immune system and/or antiretroviral medications. […] The HIV DNA copy is incorporated into the DNA of the infected lymphocyte. The lymphocytes own genetic machinery then reproduces (replicates) the HIV. Eventually, the lymphocyte is destroyed. Each infected lymphocyte produces thousands of new viruses, which infect other lymphocytes and destroy them as well. Within a few days or weeks, the blood and genital fluids contain a very large amount of HIV, and the number of CD4+ lymphocytes may be reduced substantially. Because the amount of HIV in blood and genital fluids is so large so soon after HIV infection, newly infected people transmit HIV to other people very easily.
#1 HIV Pathogenesis: The Host
https://pmc.ncbi.nlm.nih.gov/articles/PMC3426821/
Human immunodeficiency virus (HIV) pathogenesis has proven to be quite complex and dynamic with most of the critical events (e.g., transmission, CD4+ T-cell destruction) occurring in mucosal tissues. […] During the first few weeks of HIV infection, massive depletion of CD4+ T cells occurs in the gastrointestinal tract, leading to a leaky gut. […] Host defenses undoubtedly play an important role in the course of HIV disease. […] The cellular receptors for HIV and SIV are the CD4 molecule on T cells and monocyte/macrophage lineage cells along with a chemokine receptor; most commonly CCR5 and CXCR4. […] It is now evident in SIV-infected macaques and HIV-infected humans that mucosal tissues are not only primary sites of viral transmission but also the major sites for viral replication and CD4+ T-cell destruction, regardless of route of transmission.
#1 The mechanism of HIV entry to the host cell – Glycopedia
https://glycopedia.eu/echapter/the-mechanism-of-hiv-entry-to-the/
The host cell infection by HIV starts by the entry of the virus into the cell. The major target cells of HIV are CD4+ T lymphocytes, which also express chemokine receptors CCR5 and CXCR4 that are exploited by HIV to enter the cells, hence also called HIV co-receptors. The virus entry starts with the adhesion of the virion to the target cell and ends with the fusion of the cell and viral membranes followed by delivery of the viral core into the cytoplasm. […] Attachment of the virion can be relatively nonspecific, for instance, HIV envelope protein (Env, the trimer of gp120 and gp41 heterodimers, where gp41 initially is hidden) can interact with negatively charged cell-surface heparan sulfate proteoglycans. More specific adhesion includes interactions between Env and a4b7 integrin or CLRs such as DC-SIGN. Either way of adhesion most likely brings Env into close proximity with the host CD4 and a coreceptor, leading to the fusion of viral and target cell membranes.
#1 The mechanism of HIV entry to the host cell – Glycopedia
https://glycopedia.eu/echapter/the-mechanism-of-hiv-entry-to-the/
Env binding to its primary receptor CD4, a member of the immunoglobulin superfamily that enhances T-cell receptor (TCR)-mediated signaling, is absolutely required for the infection. This binding event induces rearrangements in gp120 subunit of Env, which ultimately result in V3 loop repositioning and bridging sheet exposure that are essential for coreceptor engagement. Subsequent binding to the coreceptor, CCR5 or CXCR4 depending on the virus strain R5 or R4, triggers the membrane fusion potential of Env, and usually is followed by the surfing of the virus particle to the site where productive membrane fusion may occur. […] Coreceptor-bound Env undergoes conformational changes that expose the hydrophobic gp41 fusion peptide, which then inserts into the host cell membrane and folds to form six helix bundle. The latter is the driving force that brings the opposing membranes into close proximity, resulting in the formation of a fusion pore. […] Once the virus enters the cell, it can start its replication and productive infection, which ultimately lead to the depletion of CD4+ T lymphocytes in the body, and thus the acquired immunodeficiency syndrome (AIDS).
#1 HIV Infection and AIDS: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/211316-overview
Visible effects of HIV infection come in the form of disrupted lymph-node architecture. […] HIV replicates in activated T cells (its promotor contains a nuclear factor kappa B [NF-kappa-B] binding region, the same protein that promotes other proteins in activated T cells and macrophages), and activated T cells migrate to the lymph nodes. […] As such, much of the viral replication occurs outside of the peripheral blood, even though serum viral load is still a useful surrogate marker of viral replication.
#1 Human Immunodeficiency Virus (HIV) Infection – Infectious Diseases – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/infectious-diseases/human-immunodeficiency-virus-hiv/human-immunodeficiency-virus-hiv-infection
With each cell division, the integrated proviral DNA is duplicated along with the host DNA. […] Subsequently, the proviral HIV DNA can be transcribed to HIV RNA and translated to HIV proteins, such as the envelope glycoproteins 41 and 120. […] These HIV proteins are assembled into HIV virions at the host cell inner membrane and budded from the cell surface within an envelop of modified human cell membrane. […] Each host cell may produce thousands of virions. […] After budding, protease, another HIV enzyme, cleaves viral proteins, converting the immature virion into a mature, infectious virion. […] Infected CD4+ lymphocytes produce 98% of plasma HIV virions. […] The HIV average half-life in plasma is about 36 hours, about 24 hours intracellularly, and about 6 hours as an extracellular virus.
#1 Pathogenesis of HIV Infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3892619/
Two main chemokine receptors have been identified to play a major role in HIV entry, CCR5 and CXCR4 (or fusin). […] The discovery of chemokine receptors as essential coreceptors required for HIV entry has to a large extent rationalised the basis of cellular tropism and better defined HIV entry into different cells. […] CCR5 is present on a broad range of cells that can be infected by HIV, including T cells, monocytes and macrophages. […] Different HIV strains may be encountered in the body of the patients which can be classified into three variants: M-, T- and dual-tropic. […] M-tropic HIV variants can infect monocytes, macrophages and T lymphocytes through using CCR5 (R5), but not T cell lines as these express primarily CXCR4. […] T-tropic variants, which use CXCR4 (X4) as their principal coreceptor readily, infect T-cell lines and T lymphocytes but not macrophages.
#1 Pathogenesis of HIV Infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3892619/
Thus the current classification of cellular tropism of HIV-1 relies on the differential expression of CCR5 and CXCR4 in monocytes/macrophages and T-cell lines. […] CCR5 is important for NSI M-tropic strains (R5NSI) of HIV, most commonly observed in early stage of infection. […] On the other hand, CXCR4 mostly is associated with SI strains (X4SI) which are more pathogenic and they appear in some individuals with more aggressive disease. […] The dual-tropic HIV-1 variants infect both monocytes/macrophage and T-cell lines either through CCR5 or CXCR4 (R5X4) respectively. […] Macrophages act as major reservoirs for HIV-1 in tissues of the body. […] HIV infected macrophages may be found in brain, lungs, lymph nodes, skin, bone marrow and blood of seropositive individuals. […] They are the main source of productive infection in brain, and HIV infected macrophages in lymph nodes produce large amounts of viral particles.
#1 Pathogenesis of HIV Infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3892619/
Infection with HIV-1 persists for weeks or months after commencement of highly active retroviral therapy (HAART). […] Monocytes/macrophages are believed to serve as vehicles for dissemination of HIV between different tissues of the body. […] The variability in susceptibility and productivity of infection shown here between neonatal and adult cells may be due to differences in the expression of chemokine receptors such as CCR5, CXCR4, CCR3 and CD4. […] Progression of acute HIV-1 infection to AIDS is accompanied by immune dysregulation and susceptibility to OIs. […] Many distinct strains of HIV-1 have been isolated, and their variability in biological, serological, and molecular features indicate the virus is highly heterologous. […] R5 M-tropic strains are dominant in the early stages of infection, and more importantly they persist to advanced stages of disease.
#1 Pathogenesis of HIV Infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3892619/
In a progressive study we have shown the importance of macrophages, the persistence and role of R5 M-tropic HIV-1 strains in disease progression. […] These R5 strains from the advanced stage of disease are biologically fit and more infectious than those derived from the early time of infection. […] They are able to infect productively monocytes and macrophages. […] On the other hand, the R5 variants appear to be restricted in replication, particularly in undifferentiated monocytes at the level of viral entry. […] Thus, R5 from patients with AIDS seem to have an enhanced cytopathic activity and higher affinity for binding to CD4 and/or CCR5. […] Years after chronic infection is established, CXCR4 utilizing strains emerge in approximately 40% of infected individuals. […] The importance of the emergence of X4 strains in late stages of infection has always been directed towards their role in in immunodeficiency and rapid progression to AIDS.
#1 Pathophysiology of HIV/AIDS – Wikipedia
https://en.wikipedia.org/wiki/Pathophysiology_of_HIV/AIDS
HIV is commonly transmitted via unprotected sexual activity, blood transfusions, hypodermic needles, and from mother to child. Upon acquisition of the virus, the virus replicates inside and kills T helper cells, which are required for almost all adaptive immune responses. […] When the CD4 lymphocyte count falls below 200 cells/ml of blood, the HIV host has progressed to AIDS, a condition characterized by deficiency in cell-mediated immunity and the resulting increased susceptibility to opportunistic infections and certain forms of cancer. […] After the virus enters the body there is a period of rapid viral replication, leading to an abundance of virus in the peripheral blood. […] This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. […] During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4+ T cell depletion, although apoptosis may also be a factor.
#1 Understanding the Pathogenesis of HIV: Key Mechanisms and Implications
https://healthokglobal.com/pathogenesis-of-hiv
The depletion of CD4+ T cells is a key feature of HIV infection and a major factor in the progression to AIDS. The mechanisms of CD4+ T cell depletion include direct viral killing of infected cells, immune-mediated killing of infected cells, and the bystander effect, where uninfected cells are also killed. The loss of CD4+ T cells impairs the immune system’s ability to respond to infections and malignancies. […] HIV establishes latent reservoirs in various tissues, including lymphoid tissues, the central nervous system, and the gastrointestinal tract. Latent reservoirs consist of infected cells that harbor the virus but do not produce new virions. These reservoirs are a major obstacle to curing HIV, as the virus can persist in these cells despite antiretroviral therapy. […] HIV infection leads to a range of immune dysfunctions, including impaired antibody production, reduced cytotoxic T cell responses, and dysregulation of cytokine production. These dysfunctions contribute to the increased susceptibility to opportunistic infections and cancers seen in HIV-infected individuals.
#1 Pathophysiology of HIV/AIDS – Wikipedia
https://en.wikipedia.org/wiki/Pathophysiology_of_HIV/AIDS
Continuous HIV replication results in a state of generalized immune activation persisting throughout the chronic phase. […] A major cause of CD4+ T cell loss appears to result from their heightened susceptibility to apoptosis when the immune system remains activated. […] CD4 T-cell depletion and chronic inflammation are the two signature events that drive HIV pathogenesis and progression to AIDS. […] The CD4-gp120 interaction is also permissive to other viruses like Cytomegalovirus, Hepatitis virus, Herpes simplex virus, etc. These viruses lead to further cell damage i.e. cytopathy.
#1 Pathogenesis of Human Immunodeficiency Virus-Mycobacterium tuberculosis Co-Infection
https://www.mdpi.com/2077-0383/9/11/3575
Late-stage HIV infection similarly involves both type 1 interferons and interferon stimulated gene 15 (ISG15) protein as part of the antiviral response. […] There is evidence that ISG15 protein, a protein released by type 1 interferons, inhibits HIV replication by disrupting the ubiquitination of Gag required for HIV replication. […] HIV recruits caspase 3 to initiate cell apoptosis in active permissive CD4+ T cells. […] HIV also destroys inactive nonpermissive CD4+ T cells by recruitment of caspase 1 to induce pyroptosis, an apoptotic mechanism accompanied with markedly increased levels of inflammation. […] This mechanism may help explain the nonspecific symptoms such as acute fever, diarrhea, malaise, fatigue, and weight loss, that occur shortly after contracting HIV. […] HIV manipulates surface receptor CCR5 for entry into DCs, a receptor that is highly expressed in CD11C+ DCs, a DC subgroup found exclusively in the human genital region. […] HIV exploits the DCs antigen presentation abilities to present virion fractions to CD4+ T cells. […] HIV-induced ROS also leads to chronic inflammation that triggers the immune response and may increase the likelihood of developing comorbidities similar to that of ageing.
#1 HIV infection | Nature Reviews Disease Primers
https://www.nature.com/articles/nrdp201535
Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. […] HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. […] HIV induces thymus depletion in vivo. […] Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. […] Systemic effects of inflammation on health during chronic HIV infection.
#1 Innate immune recognition and activation during HIV infection | Retrovirology | Full Text
https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-7-54
This loss is largely irreversible and has profound immunological consequences, eventually manifesting as failure of the host immune defences and progression to AIDS later during infection. […] The ultimate consequence of immune activation is depletion of CD4+ T cells by different mechanisms, including a decrease in CD4+ and CD8+ T cell half-life, abnormal T cell trafficking, clonal exhaustion of T cells, and drainage of memory T cell pools. […] Nevertheless, CD4+ T cells are profoundly depleted and replaced by short-lived T cells with a more limited regenerative potential. […] HIV infection also profoundly affects blood and tissue B cells by inducing early class switching in polyclonal B cells, massive B cell apoptosis, and loss of germinal centers in lymphoid tissue. […] It seems reasonable to assume that PRR-triggered inflammation and type I IFN production induced by HIV or opportunistic pathogens represent ample possibility for initiating and perpetuating this disadvantageous pathological immune activation leading to progressive immunodeficiency.
#1 HIV Pathogenesis: The Host
https://pmc.ncbi.nlm.nih.gov/articles/PMC3426821/
In contrast to mucosal transmission, which provides a selective barrier based on the ability of the virus to contact target cells either directly or by using existing biological processes, intravenous transmission poses no such barrier. […] It is now clear that both HIV and SIV selectively infect and destroy memory CD4+ T cells (both central and effector cells) resulting in subsequent impairment of immune responses to not only the infecting virus, but to other antigens as well. […] The potential for antiretroviral therapy (ART) to restore mucosal CD4+ T cells has only begun to be examined and has been particularly difficult to assess in acute infection. […] Despite profound immune deficiency, there is evidence of profound immune activation in HIV infection. […] The recognition that progressive HIV and SIV infection is linked to immune activation, which in turn is linked to a leaky gut, has only recently focused intense interest on the effects of HIV and SIV infection on the intestinal epithelial barrier.
#1 About HIV | HIV | CDC
https://www.cdc.gov/hiv/about/index.html
HIV (human immunodeficiency virus) is a virus that attacks the body’s immune system. Without treatment, it can lead to AIDS (acquired immunodeficiency syndrome). […] HIV treatment (antiretroviral therapy or ART) involves taking medicine as prescribed by a health care provider. You should start HIV treatment as soon as possible after diagnosis. HIV treatment reduces the amount of HIV in the blood (viral load). HIV treatment can make the viral load so low that a test can’t detect it (undetectable viral load). If you have an undetectable viral load, you will not transmit HIV to others through sex. Having an undetectable viral load also reduces the risk of HIV transmission through sharing drug injection equipment, and during pregnancy, labor, and delivery. […] When people with HIV don’t get treatment, they typically progress through three stages. But HIV treatment can slow or prevent progression of the disease. With advances in HIV treatment, progression to Stage 3 (AIDS) is less common today.
#1 The pathogenesis of HIV infection: stupid may not be so dumb after all | Retrovirology | Full Text
https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-3-60
In the mid-1990’s, researchers hypothesized, based on new viral load data, that HIV-1 causes CD4+ T-cell depletion by direct cytopathic effect. […] Despite having high levels of viremia, most SIV infections are well tolerated by their natural hosts. […] The degree of immunodeficiency associated with HIV-1 infection, as defined by the onset of opportunistic diseases, correlates closely with plasma CD4+ T-cell counts. Moreover, the rate at which immunosuppression develops also closely reflects the levels of HIV-1 RNA in plasma, such that the higher the HIV-1 viral load, the greater the loss of circulating CD4+ T-cells per year. […] It is now widely appreciated that both HIV-1 infection in humans, and simian immunodeficiency virus (SIV) infection in rhesus macaques, are associated with destruction of the vast majority of memory CD4+ T-cells in the gastrointestinal tract in the first few weeks after infection.
#1 Innate immune recognition and activation during HIV infection | Retrovirology | Full Text
https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-7-54
Importantly, the depletion of CD4+ memory T cells is not restricted to T cells of mucosal origin, although quantitatively most cells are lost from the mucosa, because the greatest number of T cells is resident in this location. […] As to the cellular mechanism underlying this massive CD4+ T cell depletion, another study in SIV-infected rhesus macaques found that SIV exploits a large resident population of CD4+ memory T cells to produce high levels of virus that both directly, through lytic infection, and indirectly, through Fas-mediated apoptosis of infected and uninfected cells, deplete the majority of CD4+ T cells in GALT within the first 3 weeks of infection. […] Thus, acute HIV infection is accompanied by a selective and dramatic depletion of CD4+CCR5+ memory T cells predominantly from mucosal surfaces.
#1 Pathogenesis of primary HIV infection – HIV Management Guidelines
https://hiv.guidelines.org.au/management/primary-hiv-infection/primary-hiv-infection-pathogenesis-of-primary-hiv-infection/
HIV selectively infects and destroys memory CD4+ T cells in early infection, with rapid depletion of these cells in the lymphoid tissues, gut and genitourinary tracts. If not reversed early, this damage leads to distortion of the architecture within lymphoid tissues and then fibrosis, which is difficult to reverse. This results in impairment of immune responses not only to HIV, but to other antigens as well, eventually leading to the profound immunodeficiency of AIDS. Nevertheless, a robust CD4+ T cell response in PHI occurs simultaneously with, or even before, the CD8+ T cell response and is associated with maintenance of effective immunity. […] Some infected CD4+ T cells become resting cells before the virus causes cell death. This allows the integrated virus to become latent, establishing a viral reservoir that can be reactivated at a later time point. This reservoir is established within the earliest days of primary infection and persists for the lifetime of the patient, but can be limited in its size by early initiation of ART.
#1 HIV Infection and AIDS: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/211316-overview
Immune responses to certain antigens begin to decline, and the host fails to adequately respond to opportunistic infections and normally harmless commensal organisms. […] Because the defect preferentially affects cellular immunity, the infections tend to be nonbacterial (fungal, viral). […] Gut-associated lymphoid tissue (GALT) plays a role in HIV replication. […] GALT has been shown to be a site of early viral seeding and establishment of the proviral reservoir. […] This reservoir contributes to the difficulty of controlling the infection, and efforts to reduce the levels of HIV provirus through sustained antiretroviral therapy (alone or in combination with interleukin-2 activation of resting HIV-infected T cells) have consistently failed. […] A feature of HIV replication in GALT is that it is compartmentalized, even among different areas of the gut.
#1
https://link.springer.com/article/10.1007/s11904-010-0070-4
HIV can infect the brain and impair central nervous system (CNS) function. […] Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. […] HIV is neurovirulent, with clinically relevant central nervous system (CNS) symptoms observed in more than 50% of patients not receiving combination antiretroviral therapy (cART). […] Blood tests such as CD4+ lymphocyte counts and plasma HIV RNA levels are typically used in clinical settings to estimate the severity of HIV disease and cART effectiveness. […] HIV quickly enters the brain after initial exposure, probably through infected monocytes and lymphocytes that cross the blood brain barrier (BBB). […] Although neurons are not infected by HIV, they can be injured via indirect mechanisms, including viral proteins, such as gp120 and tat, and neurotoxins resulting from the neurological immune response.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/news/20241118/Study-uncovers-key-mechanism-behind-HIV-latency.aspx
An immune response that likely evolved to help fight infections appears to be the mechanism that drives human immunodeficiency virus (HIV) into a latent state, lurking in cells only to erupt anew, researchers at Duke Health report. […] HIV has proven to be incurable because of a small number of latently HIV-infected T-cells that are untouched by both antiviral drugs and the immune response. […] Cullen and his team found that, in a small number of infected cells, the SMC5/6 protein complex initiates a process that silences the DNA provirus before it integrates into a host cell chromosome. These proviruses remain inert even after integration and result in latent infections, lying low until prompted to erupt into an active infection. […] Our research suggests that latency results not from any intrinsic properties of the infecting HIV but rather from an unfortunate side effect of a cellular innate immune response that probably evolved to silence invasive foreign DNA.
#1 Advances in the immunopathogenesis of hiv infection | Enfermedades Infecciosas y MicrobiologÃa ClÃnica
https://www.elsevier.es/es-revista-enfermedades-infecciosas-microbiologia-clinica-28-articulo-advances-in-the-immunopathogenesis-of-hiv-infection-13070249
HIV is capable of infecting its target cells latently and thus completely escapes immunological surveillance by not expressing viral products in the membrane. Furthermore, reactivation-reinfection processes are extraordinarily fast and they take place in the T-cell parafollicular areas of lymphoid organs, which present an ideal cellular microenvironment for the process of infection and viral propagation. […] Recent years have seen extremely important advances in our understanding of the immune pathogenesis of HIV infection. It can be said that AIDS immunology is finally developing along solid scientific lines. Nevertheless, there remain two huge challenges: the impossibility of eradicating the infection and the absence of therapeutic or preventive vaccines against HIV.
#1 Macrophages: Key Cellular Players in HIV Infection and Pathogenesis
https://www.mdpi.com/1999-4915/16/2/288
Although cells of the myeloid lineages, including tissue macrophages and conventional dendritic cells, were rapidly recognized, in addition to CD4+ T lymphocytes, as target cells of HIV-1, their specific roles in the pathophysiology of infection were initially largely neglected. […] However, numerous studies performed over the past decade, both in vitro in cell culture systems and in vivo in monkey and humanized mouse animal models, led to growing evidence that macrophages play important direct and indirect roles as HIV-1 target cells and in pathogenesis. It has been recently proposed that macrophages are likely involved in all stages of HIV-1 pathogenesis, including virus transmission and dissemination, but above all, in viral persistence through the establishment, together with latently infected CD4+ T cells, of virus reservoirs in many host tissues, the major obstacle to virus eradication in people living with HIV.
#1 Macrophages: Key Cellular Players in HIV Infection and Pathogenesis
https://www.mdpi.com/1999-4915/16/2/288
Infected macrophages are indeed found, very often as multinucleated giant cells expressing viral antigens, in almost all lymphoid and non-lymphoid tissues of HIV-1-infected patients, where they can probably persist for long period of time. […] The complexities extend beyond the immediate impact on viral replication, delving into broader considerations of how HIV-1 manipulates macrophages both as viral host cells and reservoirs. […] Therefore, the general goal of this review is to provide an overview of the specific roles of macrophages as key cellular players in HIV-1 infection and pathogenesis. […] While it is generally accepted that HIV-1 primarily targets CD4+ T cells, cells of the myeloid lineage, including tissue macrophages, conventional dendritic cells (DCs), and bone osteoclasts (OCs), which all express the CD4 receptor as well as the CXCR4 and CCR5 coreceptors required for virus entry, are increasingly recognized as important productively HIV-1-infected target cells involved in the different steps of HIV-1 pathogenesis.
#1 Macrophages: Key Cellular Players in HIV Infection and Pathogenesis
https://www.mdpi.com/1999-4915/16/2/288
Infected macrophages can then efficiently transfer viruses to uninfected CD4+ T cells across a virological synapse. […] However, additional investigations seeking to elucidate the specific role of macrophages in HIV-1 transmission, particularly in mucosal tissues, are needed to shed light on the early events that contribute to the establishment of an infection. […] Finally, infected macrophages are not susceptible to the virus-induced cytopathic effect, and can thus participate, together with latently infected CD4+ T cells, in the early establishment and persistence of virus reservoirs in numerous host tissues. […] Importantly, investigations in experimentally infected animal models have confirmed the presence of infected macrophages in many tissues, as well as their critical role in pathogenesis.
#1 Macrophages: Key Cellular Players in HIV Infection and Pathogenesis
https://www.mdpi.com/1999-4915/16/2/288
The main role of the HIV-1 auxiliary proteins, such as Nef, Vif, and Vpr, is to prevent the incorporation of host cell factors into progeny virus particles; these factors can act in the next cycle of infection to restrict the early steps of virus replication, including virus fusion at the cell surface, uncoating, reverse transcription, and then nuclear translocation and integration of the viral DNA. […] In contrast, we have shown that the cellâcell fusion process for cell-to-cell virus spreading from infected CD4+ T cells to myeloid cells resulted in the phosphorylation of SAMHD1, allowing for very efficient virus replication and spreading in macrophages and DCs. […] Infected macrophages are indeed frequently detected as multinucleated cells in the CNS and other tissues of HIV-1-infected patients and SIV-infected monkeys.
#1 AIDS: discovery of a new mechanism induced by HIV to modulate the immune system | Institut Pasteur
https://www.pasteur.fr/en/aids-discovery-new-mechanism-induced-hiv-modulate-immune-system?language=fr
Researchers from the Pasteur Institute and the CNRS* have revealed a novel mechanism utilized by the AIDS virus (HIV) to modulate the host immune response. […] They have shown that the virus substantially reduces contacts between the HIV-1 infected T lymphocytes and other cells of the immune system. […] Their work has shown that, in the T lymphocyte, HIV blocks the intracellular transport of molecules that are essential to immune synapse formation. […] Conclusion: contacts between the T lymphocytes and antigen presenting cells are altered. This modifies the T lymphocyte response. […] The researchers have identified an HIV component, the viral protein called Nef, whose role is still poorly understood, as being responsible for this phenomenon.
#1 Pathogenesis of Human Immunodeficiency Virus-Mycobacterium tuberculosis Co-Infection
https://www.mdpi.com/2077-0383/9/11/3575
HIV is known to gradually deplete native and memory CD4+ T cells and ultimately result in acquired immunodeficiency syndrome (AIDS). […] HIV infection has been demonstrated to inhibit T helper 1 (Th1) cell activity and increase T helper 2 cell (Th2) activity. […] This aberration is often referred to as a Th1/Th2 cell switch, a phenomenon that Romangnani and colleagues suggest is due to preferential HIV replication within Th2-like cells over Th1 cells that stimulate their proliferation. […] The depletion of CD4+ T cells severely compromises the hostâs immune response, leaving the individual vulnerable to opportunistic infections such as TB. […] In an acute HIV infection, type 1 interferons play a critical role in response to HIV infection of T cells by inducing a pro-inflammatory state that slows viral replication.
#1 KoreaMed Synapse
https://synapse.koreamed.org/articles/1144993
Nef-induced activation of these transcriptional factors also promote the initiation of viral transcription leading to viral proliferation. […] Cell mobility inhibition It has been reported that HIV-1 Nef inhibits the extracellular secretion of the stromal derived factor (SDF) to inhibit T cell mobility, followed by a decreased immunological activity of T cells. […] These studies provided evidences that Nef inhibit T-cell chemotaxis for immunological T-cell function and induces immune deficiency. […] Vesicle membrane trafficking disturbance In T cells expressed with HIV-1 Nef, membrane hypermobility was observed as if the activation of endocytosis and exocytosis seen in activated T cells. […] T cell receptor signal disturbance The T cell receptor (TCR) signal triggered by TCR-CD3 activation, express the IL-2 chemokine through the Lck Zap70 PLC IP3 IP3 receptor calcium release NFAT/NF-b IL-2.
#1 Understanding the Pathogenesis of HIV: Key Mechanisms and Implications
https://healthokglobal.com/pathogenesis-of-hiv
HIV employs several strategies to evade the host’s immune response. These include high mutation rates that lead to the rapid evolution of viral variants, the downregulation of host cell surface molecules involved in immune recognition, and the establishment of viral reservoirs. These evasion mechanisms complicate the development of effective vaccines and therapies. […] Understanding the pathogenesis of HIV is crucial for developing effective treatments. Antiretroviral therapy (ART) targets various stages of the viral life cycle, including entry, reverse transcription, integration, and protease activity. While ART can suppress viral replication and improve immune function, it cannot eradicate latent reservoirs. Research is ongoing to develop strategies to eliminate these reservoirs and achieve a functional cure for HIV.
#1 KoreaMed Synapse
https://synapse.koreamed.org/articles/1144993
This study aims to introduce the virulence-inducing mechanism of the HIV-1 Nef and propose new therapeutic strategies against HIV-1 through Nef targeting. […] CD4 down-regulation CD4 is a T-cell membrane protein which binds to HIV-1 gp120 to facilitate HIV-1 infection, whereas, CD4 expression is diminished by HIV-1 infection. […] It was defined that the down-regulation of CD4 was caused by Nef expression after HIV-1 infection in an initial study. […] The detail mechanism of CD4 down-regulation was revealed that CD4 on the surface membrane was internalized and degraded through the endosomal/lysosomal pathway. […] It has been known that the adapter protein 2 (AP-2), which is a clathrin-associated adaptor protein acting on endocytosis, plays an important role in the inhibition of CD4 expression by Nef.
#1 Human Immunodeficiency Virus (HIV) | British Society for Immunology
https://www.immunology.org/public-information/bitesized-immunology/pathogens-disease/human-immunodeficiency-virus-hiv
There are various reasons which can contribute to the failure of the immune system to control HIV infection and prevent AIDS development. By infecting CD4+ T cells, HIV is able to replicate predominantly in activated T cells and paralyse one of the main components of adaptive immune system. HIV can also establish latent infection in CD4+ T cells and remain invisible to CD8+ T cells and therefore replication can occur later in the infection and generate new virions.
#1 KoreaMed Synapse
https://synapse.koreamed.org/articles/1144993
Human immunodeficiency virus-1 (HIV-1) encodes an accessory protein Nef. […] The pivotal role of Nef in disease progression has been discovered in primary culture and in vivo studies. […] Since it is already known that the nef-deleted virus is associated with long-term non-progression (LTNP), the roles of Nef linked to viral virulence were emphasized to develop an agent capable of inhibiting the progression of acquired immunodeficiency syndrome (AIDS). […] Nef plays multifaceted roles in host cell activities, which are recognized as the key functions of Nef-induced AIDS progression. […] Nef down-regulates the surface expression of several immune proteins including CD4, major histocompatibility complex class I (MHC-I/II), CD3. […] Nef disturbs the actin dynamics linked to vesicle trafficking and cell movement, and modulates the T-cell activation signaling associated with viral transcription.
#1 KoreaMed Synapse
https://synapse.koreamed.org/articles/1144993
Furthermore, it is more worthy note that CD4-down regulation by Nef is closely associated to host immune dysfunction leading to AIDS. […] MHC-I down-regulation It may be possible that cytotoxic T lymphocytes (CTL) response eliminates HIV-1 infected cells. […] Nef together with MHC-I from the plasma membrane into the trans Golgi network (TGN) by binding to PACS-2, inhibited MHC-I to move out to the cell membrane, and finally prevented expose of MHC-I on the surface membrane. […] This mechanism of Nef may disable CTL response to eliminate HIV-1 infected cells, thereby promoting virulence by increasing the proliferation and concentration of the virus and disturbing the immune system. […] T cell activation signaling Proliferation of HIV-1 is closely related with the T-cell activation signals including transcription factors of NF-b, AP1 and NFAT which are activated by Nef expression.
#1
https://link.springer.com/article/10.1007/s11904-010-0070-4
HIV encephalopathy is characterized by gliosis, microglial nodules, perivascular macrophage accumulation, and the presence of multinucleated giant cells. […] Immune activation (encephalitis) is often out of proportion to the amount of HIV virus present in the brain. […] The demonstration that these cells transition from bone marrow is consistent with an informative case of HAD in humans where the viral signature in deep brain structures was most consistent with that in bone marrow and circulating monocytes and a finding that peripheral monocytes HIV DNA levels correlate to HAND in the current era. […] Together, these data raise concern that peripheral reservoirs continue to play an active role in brain injury despite cART. […] HIV RNA was identified in about half of subjects at autopsy, despite most subjects having access to cART.
#1 HIV infection | Nature Reviews Disease Primers
https://www.nature.com/articles/nrdp201535
More than 75 million people worldwide have been infected with human immunodeficiency virus (HIV), and there are now approximately 37 million individuals living with the infection. […] Untreated HIV replication causes progressive CD4+ T cell loss and a wide range of immunological abnormalities, leading to an increased risk of infectious and oncological complications. […] HIV infection also contributes to cardiovascular disease, bone disease, renal and hepatic dysfunction and several other common morbidities. […] Viral suppression enables immune recovery and the near elimination of the risk for developing acquired immune deficiency syndrome (AIDS). […] Despite effective treatment, HIV-infected individuals have a higher than expected risk of heart, bone, liver, kidney and neurological disease.
#1 Pathogenesis
https://www.hivwasting.com/en/hivwasting/hcp/pathogenesis.html
HIVAW has been attributed in part to endocrine dysfunction. Disruptions of the hormonal regulatory axes together with abnormal hormone levels lead to problems regulating the metabolism of proteins, lipids, and carbohydrates which can lead to loss of lean body mass, weight loss, and loss of energy. […] Both the innate and adaptive immune systems can become dysfunctional in response to HIV infection. Even when the virus is controlled, latently infected cells remain. Dysregulation of cytokine production is a key immunological abnormality associated with HIVAW. […] Even in HIV-positive patients with undetectable viral loads, the gut-associated lymphoid tissue, or GALT, remains a latent reservoir for the virus. This leads to changes in the structure and function of the gut that may contribute to HIVAW.
#1 SciELO – Public Health – HIV virology and pathogenetic mechanisms of infection: a brief overview HIV virology and pathogenetic mechanisms of infection: a brief overview
https://www.scielosp.org/article/aiss/2010.v46n1/5-14/
Infected cells can undergo lysis or allow the establishment of latent infection, particularly in macrophages and resting CD4+ T-cells, which are permanent viral reservoirs. […] The progression of the disease is characterized by the destruction of the lymphoid tissue architecture, which is a consequence of the virus replication and of the chronic activation of the cells of immune system. […] The further progression of the disease depends on the capacity of the host to contain virus replication and to reconstitute the pool of memory T-cells within the mucosa associated lymphoid tissue or lymph nodes. […] The most common opportunistic infections, which define the AIDS stage, are caused by Microcystis carinii, Candida albicans, Cytomegalovirus, Herpes zoster or enteropathic parasites (Criptosporidium and Giardia species, Isospora belli), which can determine life-threatening diseases.
#1 HIV-TB Pathogenesis and Treatment | SAMRC
https://www.samrc.ac.za/research/extramural-research-units/hiv-tb-pathogenesis-and-treatment
The HIV-TB Pathogenesis and Treatment Research Unit, based at the Centre for the Aids Programme of Research in South Africa (CAPRISA), researches ways to reduce the mortality rate and widespread presence of HIV and Tuberculosis (TB) co-infection. […] HIV infection is the leading cause of death in South Africa, which has the third highest HIV-related TB problem in the world, with as many as 60% of HIV patients being co-infected with TB. […] Improving the survival rate of those infected with both HIV and TB by optimising their treatment; […] Sharing reliable information on the links between HIV and TB; […] Promoting the use of clinical trial evidence in real world settings; […] Informing the countrys HIV-TB epidemic policies and practices; and […] Growing South Africas HIV-TB co-infection research community.
#1 HIV infection and malignancy: Epidemiology and pathogenesis – UpToDate
https://www.uptodate.com/contents/hiv-infection-and-malignancy-epidemiology-and-pathogenesis
Individuals living with HIV have an increased propensity to develop malignancy. The occurrence of an extremely high number of cases of Kaposi sarcoma (KS) was noted early in the AIDS epidemic and many of them had an unusually aggressive clinical course. KS was therefore included as an AIDS-defining illness in early case definitions from the Centers for Disease Control and Prevention (CDC). Non-Hodgkin lymphoma (NHL) and invasive cervical carcinoma were subsequently added as AIDS-defining conditions. […] The spectrum of neoplasia in patients living with HIV has changed in areas where the use of potent antiretroviral therapy (ART) is widespread. The incidence of KS and NHL has decreased markedly, but there has been a relative increase in tumor types that collectively are referred to as non-AIDS-defining cancers (NADCs) compared with the general population. NADCs now are a major factor contributing to mortality in people living with HIV.
#1 HIV infection and malignancy: Epidemiology and pathogenesis – UpToDate
https://www.uptodate.com/contents/hiv-infection-and-malignancy-epidemiology-and-pathogenesis
The era of potent antiretroviral therapy (ART) began in 1996 with the availability of the protease inhibitors. In most patients, ART causes both an immunologic response manifested by normalization CD4 lymphocyte counts and a virologic response with nearly complete suppression of HIV viral replication. Both immunologic and virologic responses are important in achieving at least partial immune restoration, thus decreasing the incidence of opportunistic infections, reducing the risk of developing non-Hodgkin lymphoma (NHL) or Kaposi sarcoma (KS), and prolonging survival. […] As an example of the effect of ART on cancer incidence, in a cohort study of over 42,000 HIV-positive veterans and 100,000 uninfected matched controls, cancer incidence was highest for unsuppressed HIV-positive individuals compared with uninfected controls (relative risk [RR] 2.4), lower for those with early suppression (RR 2.0), and lowest among those with long-term suppression (RR 1.52), with stronger trends for AIDS-defining versus non-AIDS-defining malignancies.
#1 Pathogenesis and Treatment of Primary HIV Infection
https://www.medscape.org/viewarticle/420654
Changes in HIV-specific responses correlated with a rise in CD4+ cell count. […] The presence of detectable cell-associated HIV RNA in two thirds of patients implies that ongoing viral replication was present despite apparently complete suppression of replication on plasma assays. […] This may be partially explained by pretreatment cell-associated HIV DNA in PBMCs, which indicated that a higher proportion of cells were infected with HIV in primary infection than in chronic infection. […] These data point to the contribution of the immune system to successful therapy during chronic infection and imply that, in the absence of an immune contribution to viral control, a more intensive drug regimen may be required. […] Host factors such as CCR5delta32 mutation may be partially protective against acquisition and subsequent progression of HIV infection.
#1 The pathogenesis of HIV infection: stupid may not be so dumb after all | Retrovirology | Full Text
https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-3-60
This lack of control then contributes to a more generalized activation of the immune system, which is seen during the chronic phase of HIV-1 infection. […] Many now believe chronic immune activation, not simply HIV-1 replication, leads to progressive depletion of the remaining CD4+ T-cells. […] Each of these new articles strongly supports the concept that immune activation, at least in part, drives CD4+ T-cell depletion, whereas viremia alone is not sufficient to cause clinically significant immunodeficiency. […] When generalized immune system activation and viremia appear together, as in the case of HIV-infected humans and SIV-infected macaques, disease occurs. […] A therapy that preserves the immune system without inhibiting virus replication would certainly be a welcome addition to currently available antiretroviral drugs that target HIV but do not adequately restore immune function.
#1
https://link.springer.com/article/10.1007/s11904-007-0002-0
Gut-associated lymphoid tissue (GALT) is an important site for early HIV replication and severe CD4+ T-cell depletion. […] Initiation of highly active antiretroviral therapy leads to incomplete suppression of viral replication and substantially delayed and only partial restoration of CD4+ T cells in GALT compared with peripheral blood. […] Persistent viral replication in GALT leads to replenishment and maintenance of viral reservoirs. […] Increased levels of inflammation, immune activation, and decreased levels of mucosal repair and regeneration contribute to enteropathy. […] Assessment of gut mucosal immune system will provide better insights into the efficacy of highly active antiretroviral therapy in immune restoration and suppression of viral reservoirs.
#1 UCSF HIV/AIDS Trial â Leukapheresis to Support HIV Pathogenesis Studies
https://clinicaltrials.ucsf.edu/trial/NCT01161199
Despite the dramatic improvements that have resulted from combination antiretroviral treatment, long-term efficacy, toxicity, cost, and the requirements for life-long adherence remain as formidable challenges. […] Also, there is emerging consensus that persistent HIV-associated disease occurs during long-term highly active antiretroviral therapy (HAART). This disease may be due to either direct drug-toxicity and/or persistent viral replication/production and/or persistent HIV-associated inflammation. […] A more complete understanding of the relationship between inflammation and viral persistence is necessary before more rationale studies of HIV eradication can be designed. […] Since the level of replication competent virus in long-term treated patients (and in elite controllers) is very small (1% of CD4 cells harbor HIV), large numbers of CD4+ T cells most be obtained from study participants in order to routinely isolate and quantify virus persistence.
#1 Event Summary – HIV Pathogenesis and Cure | EK43 – Keystone Symposia
https://virtual.keystonesymposia.org/live/849
Human Immunodeficiency Virus type 1 (HIV) is the cause of a global pandemic that has a very high mortality rate, with an estimated 35 million deaths to date. […] Optimal ART can halt viral replication, thereby preventing disease progression and allowing immune reconstitution. However, ART is not curative due the persistence of a latent form of the virus. This latent form is the major barrier to cure and the subject of an intense international research effort. […] Achieving a better understanding of the basic biology of HIV infection is likely to be essential to HIV cure efforts. […] Immune-based strategies to eliminate infected cells are an important component of many cure strategies, providing a logical connection to hold the joint conference on HIV Vaccines. […] In addition to joint sessions focusing on exciting new developments in the study of antibody and T cell responses to HIV and novel technologies that will aid future studies of HIV biology, sessions also include basic mechanisms of HIV integration and transcriptional control, strategies for reversing latency and eliminating infected cells, and trials of novel cure strategies in animal models and in patients on ART.
#1 Understanding the Pathogenesis of HIV: Key Mechanisms and Implications
https://healthokglobal.com/pathogenesis-of-hiv
The pathogenesis of HIV is a complex process involving multiple interactions between the virus and the host’s immune system. Understanding these mechanisms is essential for developing effective treatments and managing the disease. Continued research in HIV pathogenesis will pave the way for new therapeutic strategies and bring us closer to achieving a functional cure for HIV.
#1 Innate immune recognition and activation during HIV infection | Retrovirology | Full Text
https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-7-54
HIV-induced immunodeficiency is not dominated by paresis and inactivity of the immune system, but rather by chronic immune activation and high cell turnover, apoptosis, and activation-induced cell death. […] Although it is widely accepted in the field that persistent immune activation plays a central part in driving immunopathogenesis and progression to AIDS, the fundamental determinants of progressive cell loss and functional immune deficiency in HIV infection remain unexplained. […] How does acute HIV infection lead to depletion of cells in gut associated lymphoid tissue (GALT) and irreversible damage to the host immune system? […] Which molecular mechanisms may underlie the chronic immune activation eventually causing progressive immune exhaustion and profound immunodeficiency? […] Studies in SIV models and HIV-infected individuals have documented that acute SIV/HIV infection is accompanied by a massive depletion of CD4+ memory T cells, primarily in mucosal tissue, which may be explained by the high expression of the viral co-receptor CCR5 and the relatively activated state of mucosal CD4+ T cells.
#1
https://clintonwhitehouse5.archives.gov/ONAP/nas/ns_m_xb6b.html
To conduct and support research to improve the understanding of HIV and the pathogenic mechanisms of HIV disease. […] Delineate the cellular and molecular mechanisms associated with the viral immunopathogenesis of HIV-related immune dysfunction. […] Basic scientific information regarding the cellular and molecular mechanisms that underlie HIV-related immune dysfunction and viral pathogenesis is critical to all areas of AIDS research. […] Delineate the molecular and cellular mechanisms of transmission and establishment of infection and their impact on disease progression. […] The mechanisms of HIV transmission and the early events in the establishment of infection, and their relationship to disease progression, need to be better understood. […] Knowledge of AIDS-associated disease pathogenesis is urgently needed.
#2 SciELO – Public Health – HIV virology and pathogenetic mechanisms of infection: a brief overview HIV virology and pathogenetic mechanisms of infection: a brief overview
https://www.scielosp.org/article/aiss/2010.v46n1/5-14/
Studies on HIV virology and pathogenesis address the complex mechanisms that result in the HIV infection of the cell and destruction of the immune system. […] A detailed understanding of HIV structure and how it establishes infection and causes AIDS are crucial not only to identify and develop new effective drugs and vaccines, but also to define strategies for the laboratory diagnosis of HIV infection. […] The pathogenesis of HIV infection and the progression to AIDS are a consequence of the properties of the infecting virus isolate and the host’s immune response to the virus. The balance between the effectiveness of these two components determines the different outcome of the infection, from development of AIDS to long-term survival. […] HIV is mainly integrated or replicating into the infected cells, which are the main vehicles of virus transmission.
#2 HIV Infection and AIDS: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/211316-overview
HIV produces cellular immune deficiency characterized by the depletion of helper T lymphocytes (CD4 cells). The loss of CD4 cells results in the development of opportunistic infections and neoplastic processes. […] HIV-1 and HIV-2 are retroviruses in the Retroviridae family, Lentivirus genus. They are enveloped, diploid, single-stranded, positive-sense RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA. […] The specific details of the disease process that leads to AIDS are not fully understood despite considerable progress in the virology of HIV and the immunology of the human host, much of which has been driven by the urge to better understand AIDS. […] There is a specific decline in the CD4 helper T cells, resulting in inversion of the normal CD4/CD8 T-cell ratio and dysregulation of B-cell antibody production.
#2 HIV – Wikipedia
https://en.wikipedia.org/wiki/HIV
The human immunodeficiency viruses (HIV) are two species of Lentivirus (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. […] HIV infects vital cells in the human immune system, such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including pyroptosis of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8+ cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.
#2 Human Immunodeficiency Virus (HIV) | British Society for Immunology
https://www.immunology.org/public-information/bitesized-immunology/pathogens-disease/human-immunodeficiency-virus-hiv
Human immunodeficiency virus (HIV), a member of the retrovirus family, is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV invades various immune cells (e.g., CD4+ T cells and monocytes) resulting in a decline in CD4+ T cell numbers below the critical level, and loss of cell-mediated immunity – therefore, the body becomes progressively more susceptible to opportunistic infections and cancer. […] HIV infects T cells via high-affinity interaction between the virion envelope glycoprotein (gp120) and the CD4 molecule. The infection of T cells is assisted by the T-cell co-receptor called CXCR4 while HIV infects monocytes by interacting with CCR5 co-receptor. […] The cellular immune response is induced upon the entry of HIV into the target cells (e.g., T cells) and synthesis of viral proteins. MHC class I on the cell surface displays the intracellularly degraded HIV peptide fragments for recognition by T-cell receptors (TCR) on CD8+ T cells. CD8+ T cells lyse HIV infected cells and secrete cytokines, i.e. interferon-Î³ (IFN-Î³), tumor necrosis factor Î± (TNF-Î±), and chemokines, i.e. MIP-1 Î±, MIP Î² and RANTES, that inhibit virus replication and block viral entry into CD4+ T cells. Development of CD8+ T cells is crucial for control of HIV replication.
#2 HIV – Wikipedia
https://en.wikipedia.org/wiki/HIV
HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells’ membrane and also with chemokine co-receptors. […] The HIV virion enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the target cell membrane and the release of the HIV capsid into the cell. […] Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the positive-sense single-stranded RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule. The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the body’s immune system.
#2 Advances in the immunopathogenesis of hiv infection | Enfermedades Infecciosas y MicrobiologÃa ClÃnica
https://www.elsevier.es/es-revista-enfermedades-infecciosas-microbiologia-clinica-28-articulo-advances-in-immunopathogenesis-hiv-infection-13070249?referer=coleccion
Initiation of transcription of the viral genome depends on cellular factors, in particular the Rel/NF-*B family of transcription factors. […] The destruction of the CD4 lymphocytes is the most characteristic event of HIV infection. […] This is probably the most important cause of lymphocyte destruction. […] Apoptosis, or programmed cell death, is a physiological mechanism by which the cell commits suicide in a controlled way. […] There is ample experimental data to support the hypothesis that HIV can induce apoptosis both in infected lymphocytes and in non-infected lymphocytes via several mechanisms: chronic activation, interaction between receptors and the viral envelope, toxic effect of viral proteins, increase in the expression of cytotoxic ligands and synthesis of cytokines by lymphocytes and macrophages.
#2 Pathogenesis of HIV Infection
https://pmc.ncbi.nlm.nih.gov/articles/PMC3892619/
In a progressive study we have shown the importance of macrophages, the persistence and role of R5 M-tropic HIV-1 strains in disease progression. […] These R5 strains from the advanced stage of disease are biologically fit and more infectious than those derived from the early time of infection. […] They are able to infect productively monocytes and macrophages. […] On the other hand, the R5 variants appear to be restricted in replication, particularly in undifferentiated monocytes at the level of viral entry. […] Thus, R5 from patients with AIDS seem to have an enhanced cytopathic activity and higher affinity for binding to CD4 and/or CCR5. […] Years after chronic infection is established, CXCR4 utilizing strains emerge in approximately 40% of infected individuals. […] The importance of the emergence of X4 strains in late stages of infection has always been directed towards their role in in immunodeficiency and rapid progression to AIDS.
#2 HIV/AIDS – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/hiv-aids/symptoms-causes/syc-20373524
HIV damages the immune system so that the body is less able to fight infection and disease. […] HIV destroys white blood cells called CD4 T cells. These cells play a large role in helping the body fight disease. The fewer CD4 T cells you have, the weaker your immune system becomes. […] You can have an HIV infection with few or no symptoms for years before it turns into AIDS. AIDS is diagnosed when the CD4 T cell count falls below 200 or you have a complication you get only if you have AIDS, such as a serious infection or cancer. […] HIV infection weakens your immune system. The infection makes you much more likely to get many infections and certain types of cancers.
#2 Innate immune recognition and activation during HIV infection | Retrovirology | Full Text
https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-7-54
HIV-induced immunodeficiency is not dominated by paresis and inactivity of the immune system, but rather by chronic immune activation and high cell turnover, apoptosis, and activation-induced cell death. […] Although it is widely accepted in the field that persistent immune activation plays a central part in driving immunopathogenesis and progression to AIDS, the fundamental determinants of progressive cell loss and functional immune deficiency in HIV infection remain unexplained. […] How does acute HIV infection lead to depletion of cells in gut associated lymphoid tissue (GALT) and irreversible damage to the host immune system? […] Which molecular mechanisms may underlie the chronic immune activation eventually causing progressive immune exhaustion and profound immunodeficiency? […] Studies in SIV models and HIV-infected individuals have documented that acute SIV/HIV infection is accompanied by a massive depletion of CD4+ memory T cells, primarily in mucosal tissue, which may be explained by the high expression of the viral co-receptor CCR5 and the relatively activated state of mucosal CD4+ T cells.
#2 HIV Pathogenesis: The Host
https://pmc.ncbi.nlm.nih.gov/articles/PMC3426821/
Human immunodeficiency virus (HIV) pathogenesis has proven to be quite complex and dynamic with most of the critical events (e.g., transmission, CD4+ T-cell destruction) occurring in mucosal tissues. […] During the first few weeks of HIV infection, massive depletion of CD4+ T cells occurs in the gastrointestinal tract, leading to a leaky gut. […] Host defenses undoubtedly play an important role in the course of HIV disease. […] The cellular receptors for HIV and SIV are the CD4 molecule on T cells and monocyte/macrophage lineage cells along with a chemokine receptor; most commonly CCR5 and CXCR4. […] It is now evident in SIV-infected macaques and HIV-infected humans that mucosal tissues are not only primary sites of viral transmission but also the major sites for viral replication and CD4+ T-cell destruction, regardless of route of transmission.
#2 About HIV | HIV | CDC
https://www.cdc.gov/hiv/about/index.html
People receive an AIDS diagnosis when their CD4 cell count drops below 200 cells per milliliter of blood, or they develop certain illnesses (sometimes called opportunistic infections). People with AIDS can have a high viral load and may easily transmit HIV to others. People with AIDS have damaged immune systems. They can get an increasing number of other serious illnesses. Without HIV treatment, people with AIDS typically survive about three years.
#2
https://link.springer.com/article/10.1007/s11904-007-0002-0
Gut-associated lymphoid tissue (GALT) is an important site for early HIV replication and severe CD4+ T-cell depletion. […] Initiation of highly active antiretroviral therapy leads to incomplete suppression of viral replication and substantially delayed and only partial restoration of CD4+ T cells in GALT compared with peripheral blood. […] Persistent viral replication in GALT leads to replenishment and maintenance of viral reservoirs. […] Increased levels of inflammation, immune activation, and decreased levels of mucosal repair and regeneration contribute to enteropathy. […] Assessment of gut mucosal immune system will provide better insights into the efficacy of highly active antiretroviral therapy in immune restoration and suppression of viral reservoirs.
#2 HIV Pathogenesis: The Host
https://pmc.ncbi.nlm.nih.gov/articles/PMC3426821/
In contrast to mucosal transmission, which provides a selective barrier based on the ability of the virus to contact target cells either directly or by using existing biological processes, intravenous transmission poses no such barrier. […] It is now clear that both HIV and SIV selectively infect and destroy memory CD4+ T cells (both central and effector cells) resulting in subsequent impairment of immune responses to not only the infecting virus, but to other antigens as well. […] The potential for antiretroviral therapy (ART) to restore mucosal CD4+ T cells has only begun to be examined and has been particularly difficult to assess in acute infection. […] Despite profound immune deficiency, there is evidence of profound immune activation in HIV infection. […] The recognition that progressive HIV and SIV infection is linked to immune activation, which in turn is linked to a leaky gut, has only recently focused intense interest on the effects of HIV and SIV infection on the intestinal epithelial barrier.
#2 Human Immunodeficiency Virus (HIV) Infection – Infectious Diseases – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/infectious-diseases/human-immunodeficiency-virus-hiv/human-immunodeficiency-virus-hiv-infection
HIV infection destroys CD4+ lymphocytes and impairs cell-mediated immunity, increasing risk of certain infections and cancers. […] HIV can directly damage the brain, gonads, kidneys, and heart, causing cognitive impairment, hypogonadism, renal insufficiency, or cardiomyopathy. […] HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors. After attachment, HIV RNA and several HIV-encoded enzymes are released into the host cell. […] Viral replication requires that reverse transcriptase (an RNA-dependent DNA polymerase) copy HIV RNA, producing proviral DNA; this copying mechanism is prone to errors, resulting in frequent mutations and, thus, new HIV genotypes. […] Proviral DNA enters the host cells nucleus and is integrated into the host DNA in a process that involves integrase, another HIV enzyme.
#2 KoreaMed Synapse
https://synapse.koreamed.org/articles/1144993
Furthermore, it is more worthy note that CD4-down regulation by Nef is closely associated to host immune dysfunction leading to AIDS. […] MHC-I down-regulation It may be possible that cytotoxic T lymphocytes (CTL) response eliminates HIV-1 infected cells. […] Nef together with MHC-I from the plasma membrane into the trans Golgi network (TGN) by binding to PACS-2, inhibited MHC-I to move out to the cell membrane, and finally prevented expose of MHC-I on the surface membrane. […] This mechanism of Nef may disable CTL response to eliminate HIV-1 infected cells, thereby promoting virulence by increasing the proliferation and concentration of the virus and disturbing the immune system. […] T cell activation signaling Proliferation of HIV-1 is closely related with the T-cell activation signals including transcription factors of NF-b, AP1 and NFAT which are activated by Nef expression.
#2 HIV infection | Nature Reviews Disease Primers
https://www.nature.com/articles/nrdp201535
More than 75 million people worldwide have been infected with human immunodeficiency virus (HIV), and there are now approximately 37 million individuals living with the infection. […] Untreated HIV replication causes progressive CD4+ T cell loss and a wide range of immunological abnormalities, leading to an increased risk of infectious and oncological complications. […] HIV infection also contributes to cardiovascular disease, bone disease, renal and hepatic dysfunction and several other common morbidities. […] Viral suppression enables immune recovery and the near elimination of the risk for developing acquired immune deficiency syndrome (AIDS). […] Despite effective treatment, HIV-infected individuals have a higher than expected risk of heart, bone, liver, kidney and neurological disease.
#2 Human Immunodeficiency Virus (HIV) Infection – Infections – MSD Manual Consumer Version
https://www.msdmanuals.com/home/infections/human-immunodeficiency-virus-hiv-infection/human-immunodeficiency-virus-hiv-infection
When HIV infection destroys CD4+ lymphocytes, it weakens the bodys immune system, which protects against many infections and cancers. This weakening is part of the reason that the body is unable to eliminate HIV infection once it has started. However, the immune system is able to mount some response. Within a month or two after infection, the body produces lymphocytes and antibodies that help lower the amount of HIV in the blood and keep the infection under control. For this reason, untreated HIV infection may cause no symptoms or only a few mild symptoms for an average of about 10 years (ranging from 2 to more than 15 years). […] HIV also infects other cells, such as cells in the skin, brain, genital tract, heart, and kidneys, causing disease in those organs.
#2 HIV infection and malignancy: Epidemiology and pathogenesis – UpToDate
https://www.uptodate.com/contents/hiv-infection-and-malignancy-epidemiology-and-pathogenesis
The era of potent antiretroviral therapy (ART) began in 1996 with the availability of the protease inhibitors. In most patients, ART causes both an immunologic response manifested by normalization CD4 lymphocyte counts and a virologic response with nearly complete suppression of HIV viral replication. Both immunologic and virologic responses are important in achieving at least partial immune restoration, thus decreasing the incidence of opportunistic infections, reducing the risk of developing non-Hodgkin lymphoma (NHL) or Kaposi sarcoma (KS), and prolonging survival. […] As an example of the effect of ART on cancer incidence, in a cohort study of over 42,000 HIV-positive veterans and 100,000 uninfected matched controls, cancer incidence was highest for unsuppressed HIV-positive individuals compared with uninfected controls (relative risk [RR] 2.4), lower for those with early suppression (RR 2.0), and lowest among those with long-term suppression (RR 1.52), with stronger trends for AIDS-defining versus non-AIDS-defining malignancies.
#2 About HIV | HIV | CDC
https://www.cdc.gov/hiv/about/index.html
HIV (human immunodeficiency virus) is a virus that attacks the body’s immune system. Without treatment, it can lead to AIDS (acquired immunodeficiency syndrome). […] HIV treatment (antiretroviral therapy or ART) involves taking medicine as prescribed by a health care provider. You should start HIV treatment as soon as possible after diagnosis. HIV treatment reduces the amount of HIV in the blood (viral load). HIV treatment can make the viral load so low that a test can’t detect it (undetectable viral load). If you have an undetectable viral load, you will not transmit HIV to others through sex. Having an undetectable viral load also reduces the risk of HIV transmission through sharing drug injection equipment, and during pregnancy, labor, and delivery. […] When people with HIV don’t get treatment, they typically progress through three stages. But HIV treatment can slow or prevent progression of the disease. With advances in HIV treatment, progression to Stage 3 (AIDS) is less common today.
#2 Event Summary – HIV Pathogenesis and Cure | EK43 – Keystone Symposia
https://virtual.keystonesymposia.org/live/849
The goal of this conference is to bring together an amalgamation of basic and applied scientists working on functional cures and eradication of HIV in an effort to not only better understand HIV treatment strategies but also the emerging technologies and approaches that will lead to the eventual eradication of HIV from infected individuals.
#2 Understanding the Pathogenesis of HIV: Key Mechanisms and Implications
https://healthokglobal.com/pathogenesis-of-hiv
The pathogenesis of HIV is a complex process involving multiple interactions between the virus and the host’s immune system. Understanding these mechanisms is essential for developing effective treatments and managing the disease. Continued research in HIV pathogenesis will pave the way for new therapeutic strategies and bring us closer to achieving a functional cure for HIV.