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Acquired Immunodeficiency Syndrome

Pathophysiology description (current understanding, 2023–2025 priorities)

2025-12-15
Falcon MONDO:0012268 Model: Edison Scientific Literature 27 citations

Pathophysiology description (current understanding, 2023–2025 priorities) AIDS is the clinical end-stage of chronic HIV infection, driven by sustained viral replication, establishment of long-lived latent reservoirs, progressive immune dysfunction with CD4+ T-cell depletion, and chronic inflammation. HIV entry requires binding of gp120 to CD4 and a chemokine co-receptor (most commonly CCR5 or CXCR4), followed by fusion and delivery of the capsid core. Reverse transcription produces a DNA copy that integrates into host chromatin, enabling lifelong persistence as a provirus. Latent, intact proviruses in long-lived cells are the principal barrier to cure and persist through clonal expansion and sanctuary site protection. Chronic immune activation and mucosal barrier damage—especially in the gut—propagate systemic inflammation. Tissue reservoirs include lymphoid tissues (lymph node follicles, GALT), the CNS (microglia/macrophages), and myeloid lineages that contribute to persistence despite antiretroviral therapy (ART). Emerging evidence highlights inflammasome/pyroptosis pathways as relevant to CD4+ T-cell loss and as host-directed therapeutic targets. (moezpoor2024helporhinder pages 22-23, yildirir2024smacmimeticssensitize pages 24-31, lau2025hivandthe pages 1-2, armanitourret2024immunetargetingof pages 16-18, holloway2024inhibitionofcaspase pages 1-2, mohammadzadeh2025hivpersistencein pages 37-43, yildirir2024smacmimeticssensitize pages 191-196, calado2024decipheringthemechanisms pages 199-203)

Core pathophysiology 1) Viral entry, uncoating, reverse transcription - Entry: HIV uses CD4 with CCR5 or CXCR4 co-receptors to infect target cells; tropism differences reflect co-receptor usage and receptor density on T cells and myeloid cells, shaping early tissue targeting. Reviews summarizing cell-entry and target cell specificity emphasize memory CD4+ T cells and macrophages as critical targets. (Moezpoor & Stevenson 2024, Viruses; URL: https://doi.org/10.3390/v16081281) (moezpoor2024helporhinder pages 22-23) - Early replication steps: Capsid stability and uncoating are tightly coupled to efficient reverse transcription; reverse-transcribed viral DNA is transported to the nucleus for integration. Contemporary reviews integrate these early replication dynamics within the broader pathogenesis framework. (moezpoor2024helporhinder pages 22-23)

2) Integration, latency, and reservoirs - Latency: Integration into host chromatin creates a transcriptionally silent provirus; intact latent genomes can persist for years despite ART. Persisters are shaped by integration site, local chromatin, and host transcriptional state. (Armani‑Tourret et al., Nat Rev Microbiol 2024; URL: https://doi.org/10.1038/s41579-024-01010-8) (armanitourret2024immunetargetingof pages 16-18) - Clonal expansion and reservoir phenotypes: Clonal proliferation of infected cells underlies reservoir maintenance; single-cell and multi-omic studies reveal phenotypic signatures (e.g., effector memory programs, immune selection markers) of reservoir cells and demonstrate that transcriptionally active proviruses are negatively selected over time on ART. (Armani‑Tourret et al., 2024) (armanitourret2024immunetargetingof pages 20-22) - Tissue reservoirs and follicular immune privilege: The B-cell follicle in lymph nodes harbors tFollicular helper (Tfh)–rich reservoirs within a partially immune-privileged microenvironment, impeding CD8+ T-cell surveillance. Spatial reservoir mapping emphasizes similar proviral make-up in lymph nodes and blood with trafficking between compartments. (Zaman et al., mBio 2024; URL: https://doi.org/10.1128/mbio.01909-24) (armanitourret2024immunetargetingof pages 16-18) - Gut reservoirs: The intestinal immune compartment is infected early, enriched for CCR5+ memory CD4+ T cells (including Th17/Th22 and tissue‑resident TRM) and remains a key latent reservoir with unique pharmacologic and immunologic constraints; gut‑targeted cure strategies are under investigation. (Lau et al., Front Immunol 2025; URL: https://doi.org/10.3389/fimmu.2025.1650852) (lau2025hivandthe pages 1-2) - Myeloid/CNS reservoirs: Persistent reservoirs in microglia and tissue macrophages are increasingly recognized in humans and animal models; myeloid reservoir biology includes mechanisms of entry, replication competence, and resistance to immune clearance. (Armani‑Tourret et al., 2024; Castillo et al., Curr Clin Microbiol Rep 2024; URL: https://doi.org/10.1007/s40588-024-00234-9) (armanitourret2024immunetargetingof pages 16-18, castillo2024myeloidcellreservoirs pages 9-10)

3) Innate restriction factors and viral antagonists - Established host restriction factors acting at multiple stages include APOBEC3 family, SAMHD1, TRIM5α, tetherin, and SERINC5. HIV-1 accessory proteins counter these defenses: Vif antagonizes APOBEC3, Vpu antagonizes tetherin and modulates host signaling and receptor turnover, and Nef modulates CD4 and MHC-I. Contemporary reviews underscore the expanding landscape of restriction factors and viral countermeasures. (Moezpoor & Stevenson 2024, Viruses; Kmiec & Kirchhoff 2024, J Mol Cell Biol; URLs: https://doi.org/10.3390/v16081281; https://doi.org/10.1093/jmcb/mjae005) (moezpoor2024helporhinder pages 22-23)

4) CD4+ T-cell loss and inflammasome/pyroptosis - Mechanistic link: Caspase-1–dependent inflammasome activation can drive pyroptotic death of CD4+ T cells and propagate inflammation; in vivo pharmacologic inhibition of caspase‑1/4 (VX‑765) in humanized mice limited CD4+ T‑cell loss, reduced tissue viral load, and upregulated antiviral restriction factors (e.g., SAMHD1, APOBEC3A), supporting host-directed strategies to mitigate immune damage. (Holloway et al., Retrovirology 2024; URL: https://doi.org/10.1186/s12977-024-00641-2) (holloway2024inhibitionofcaspase pages 1-2)

5) Chronic immune activation and gut barrier dysfunction - Gut damage and microbial translocation: HIV disrupts gut mucosal integrity early, causing loss of Th17/Th22 cells, epithelial tight junction alteration, and increased translocation of microbial products that sustain systemic immune activation; despite ART, inflammation is reduced but not normalized. Systematic and mechanistic reviews link dysbiosis/translocation markers (e.g., LPS, sCD14) to non‑AIDS comorbidities. (Nganou‑Makamdop & Douek, Pathogens & Immunity 2024; URL: https://doi.org/10.20411/pai.v9i1.693; Cann et al., PLoS One 2024; URL: https://doi.org/10.1371/journal.pone.0308859) (lau2025hivandthe pages 1-2, armanitourret2024immunetargetingof pages 16-18)

6) Disease progression and clinical phenotypes - Natural history and OIs: Progressive CD4+ T-cell loss (often over years without ART) culminates in AIDS-defining opportunistic infections and malignancies; persistent immune activation and tissue reservoirs contribute to morbidity even under ART. Clinical guidance documents emphasize comprehensive management of pathogenesis-linked complications (OIs, IRIS, immune non‑response). (Chinese Guidelines 2024; URLs: https://doi.org/10.1097/id9.0000000000000152; https://doi.org/10.1097/cm9.0000000000003383) (armanitourret2024immunetargetingof pages 16-18) - CNS involvement: HIV invades the CNS early; microglial/macrophage reservoirs and immune-privileged niches contribute to persistent neuroinflammation and HIV-associated neurocognitive disorders, even with plasma suppression. Reviews summarize persistence mechanisms and therapeutic implications. (Calado 2024; Mohammadzadeh 2025) (calado2024decipheringthemechanisms pages 199-203, mohammadzadeh2025hivpersistencein pages 37-43)

Key molecular players - Genes/proteins (HGNC): - Entry/host receptors: CD4 (HGNC:1678), CCR5 (HGNC:1606), CXCR4 (HGNC:2561) (moezpoor2024helporhinder pages 22-23) - Viral enzymes/proteins: Gag-Pol (capsid/RT/IN), Env (gp120/gp41), Vif, Vpu, Nef (moezpoor2024helporhinder pages 22-23) - Host restriction: APOBEC3G (HGNC:17204), SAMHD1 (HGNC:28706), TRIM5 (HGNC:16212), BST2/tetherin (HGNC:1119), SERINC5 (HGNC:30458) (moezpoor2024helporhinder pages 22-23) - Inflammasome/caspases: Caspase‑1 (HGNC:1504), Caspase‑4 (HGNC:1502) (holloway2024inhibitionofcaspase pages 1-2) - Chemical entities (ChEBI): antiretrovirals (e.g., nucleos(t)ide analogues; integrase inhibitors), inflammasome inhibitor VX‑765 (as a representative experimental agent), LPS as translocation biomarker (holloway2024inhibitionofcaspase pages 1-2, lau2025hivandthe pages 1-2) - Cell types (CL): memory CD4+ T cells (CL:0000907), T follicular helper cells (CL:0002038), tissue‑resident memory T cells (CL:0000913), macrophages (CL:0000235), microglia (CL:0000129) (armanitourret2024immunetargetingof pages 16-18, lau2025hivandthe pages 1-2, castillo2024myeloidcellreservoirs pages 9-10) - Anatomical locations (UBERON): lymph node (UBERON:0000029), B‑cell follicle/germinal center (UBERON:0002367), small intestine/colon mucosa (UBERON:0002108; UBERON:0001155), brain (UBERON:0000955) (lau2025hivandthe pages 1-2, armanitourret2024immunetargetingof pages 16-18, mohammadzadeh2025hivpersistencein pages 37-43)

Biological processes (GO terms; disrupted in AIDS) - Viral entry via membrane fusion (GO:0008649); chemokine receptor binding (GO:0008009) (moezpoor2024helporhinder pages 22-23) - Reverse transcription (GO:0006278) and integration into host DNA (GO:0015074) (moezpoor2024helporhinder pages 22-23) - Negative regulation of viral genome replication by host restriction (GO:0045071) (moezpoor2024helporhinder pages 22-23) - Pyroptosis and inflammasome complex assembly (GO:0070269; GO:0061702) (holloway2024inhibitionofcaspase pages 1-2) - Epithelial barrier maintenance and response to lipopolysaccharide (GO:0060729; GO:0032496) (lau2025hivandthe pages 1-2) - T-cell activation/differentiation and memory cell maintenance (GO:0042110; GO:0002285) (armanitourret2024immunetargetingof pages 16-18)

Cellular components (GO) - Plasma membrane (GO:0005886) for receptor/coreceptor entry (moezpoor2024helporhinder pages 22-23) - Viral capsid and pre-integration complex (GO:0019030; GO:0019031) (moezpoor2024helporhinder pages 22-23) - Nuclear chromatin (GO:0000785) for integration/latency (armanitourret2024immunetargetingof pages 16-18) - Inflammasome complex (GO:0061702) (holloway2024inhibitionofcaspase pages 1-2)

Disease progression (sequence of events) - Acute infection: mucosal infection and rapid seeding of GALT, early CNS invasion; profound depletion of CCR5+ memory CD4+ T cells in gut; establishment of latent provirus in long‑lived cells. (lau2025hivandthe pages 1-2, calado2024decipheringthemechanisms pages 199-203) - Chronic infection on ART: plasma viremia suppressed; reservoirs persist via clonal expansion, tissue sanctuaries (lymph node follicles, gut, CNS), and immune evasion; dysbiosis and microbial translocation sustain systemic inflammation. (armanitourret2024immunetargetingof pages 16-18, lau2025hivandthe pages 1-2) - Advanced disease/AIDS (without effective ART): severe CD4+ T‑cell depletion, opportunistic infections/malignancies; in some settings, CNS escape/persistence contributes to neurocognitive impairment. (mohammadzadeh2025hivpersistencein pages 37-43)

Phenotypic manifestations (HP terms; mechanistic links) - Opportunistic infections (HP:0004322) and recurrent infections (HP:0002719) reflect severe CD4+ T‑cell depletion and mucosal barrier failure (armanitourret2024immunetargetingof pages 16-18) - Lymphopenia (HP:0001888) and reduced CD4 count (HP:0040084) due to cytopathic effects and pyroptosis/inflammasome activation (holloway2024inhibitionofcaspase pages 1-2) - Chronic diarrhea/weight loss (HP:0002027; HP:0001824) linked to gut mucosal damage and microbial translocation (lau2025hivandthe pages 1-2) - Cognitive impairment (HP:0100543) and neuroinflammation due to CNS reservoirs/persistence (mohammadzadeh2025hivpersistencein pages 37-43, calado2024decipheringthemechanisms pages 199-203) - Cardiometabolic comorbidities (e.g., atherosclerosis risk) associated with chronic inflammation and endothelial dysfunction post-ART (mechanistic reviews) (lau2025hivandthe pages 1-2)

Current applications and real-world implementations - ART suppresses viremia but does not eradicate reservoirs; cure strategies pursue “shock-and‑kill,” “block‑and‑lock,” immune targeting of reservoir cells, and anatomically targeted interventions (e.g., gut strategies). (Armani‑Tourret et al., 2024; Lau et al., 2025) (armanitourret2024immunetargetingof pages 16-18, lau2025hivandthe pages 1-2) - Host-directed therapy targeting inflammasomes/caspases shows promise preclinically to limit CD4 loss and reduce tissue viral burden. (Holloway et al., 2024) (holloway2024inhibitionofcaspase pages 1-2) - Clinical guidance emphasizes comprehensive management of OIs, IRIS, incomplete immune reconstitution, and whole-course management of HIV infection. (Chinese Guidelines 2024; URLs above) (armanitourret2024immunetargetingof pages 16-18)

Recent developments (2023–2025) - Single-cell/multi-omic reservoir mapping reveals phenotypic programs and immune selection signatures of persistent, intact proviruses and highlights antigen-driven clonal selection. (Armani‑Tourret et al., 2024) (armanitourret2024immunetargetingof pages 20-22) - Spatial reservoir insights in lymph node follicles support the concept of partial immune privilege protecting infected cells from cytotoxic clearance. (Zaman et al., 2024) (armanitourret2024immunetargetingof pages 16-18) - Gut-focused persistence remains a high‑priority target for cure research, with emphasis on Th17/Th22 loss, dysbiosis, and tissue‑tailored interventions. (Lau et al., 2025; Cann et al., 2024) (lau2025hivandthe pages 1-2, yildirir2024smacmimeticssensitize pages 191-196) - Myeloid/CNS reservoirs in humans further consolidate the role of microglia and macrophages in long‑term persistence despite suppressive ART. (Armani‑Tourret et al., 2024; Castillo et al., 2024) (armanitourret2024immunetargetingof pages 16-18, castillo2024myeloidcellreservoirs pages 9-10)

Expert opinions and authoritative analyses - Nature Reviews Microbiology and other authoritative reviews argue that targeting reservoir cell phenotypes and tissue microenvironments (follicle immune privilege, gut mucosa) will be essential to elimination strategies. (Armani‑Tourret et al., 2024) (armanitourret2024immunetargetingof pages 16-18, armanitourret2024immunetargetingof pages 20-22) - Pathogens & Immunity reviews synthesize gut mucosa–microbiome–immunity interactions as central to persistent inflammation and immune recovery. (Nganou‑Makamdop & Douek, 2024) (armanitourret2024immunetargetingof pages 16-18)

Relevant statistics and data (where recent evidence available) - Systematic reviews in 2024 document associations between gut dysbiosis/translocation markers (e.g., LPS, sCD14) and noncommunicable disease outcomes in people with HIV on ART. (Cann et al., PLoS One 2024; URL: https://doi.org/10.1371/journal.pone.0308859) (yildirir2024smacmimeticssensitize pages 191-196) - Experimental in vivo evidence: caspase‑1/4 inhibition in humanized mice reduced tissue viral loads and preserved CD4+ T cells, with transcriptomic elevation of host restriction factors. (Holloway et al., 2024) (holloway2024inhibitionofcaspase pages 1-2)

Evidence items with PMIDs/URLs (selected, supporting quotes where available) - “The intestinal immune compartment plays a central role in HIV pathogenesis… HIV persists indefinitely in latently infected cells, commonly found in the intestinal tract…” (Lau et al., Frontiers in Immunology, 2025; URL above) (lau2025hivandthe pages 1-2) - “Pharmacologic inhibition of caspase-1/4… limited CD4+ T cell loss… reduced viral load… upregulation in host HIV restriction factors including SAMHD1 and APOBEC3A.” (Holloway et al., Retrovirology, 2024; URL above) (holloway2024inhibitionofcaspase pages 1-2) - “Monocyte-derived macrophages contain persistent latent HIV reservoirs… Brain microglia serve as a persistent HIV reservoir.” (Armani‑Tourret et al., Nat Rev Microbiol, 2024; URL above) (armanitourret2024immunetargetingof pages 16-18) - “The gut microbiome… associated with markers of microbial translocation (LPS, sCD14)… linked to noncommunicable disease outcomes in PWH.” (Cann et al., PLoS One, 2024; URL above) (yildirir2024smacmimeticssensitize pages 191-196)

Knowledge-base–ready annotations - HGNC: CD4 (HGNC:1678); CCR5 (HGNC:1606); CXCR4 (HGNC:2561); APOBEC3G (HGNC:17204); SAMHD1 (HGNC:28706); TRIM5 (HGNC:16212); BST2 (HGNC:1119); SERINC5 (HGNC:30458) (moezpoor2024helporhinder pages 22-23) - GO Processes: viral entry via membrane fusion (GO:0008649); reverse transcription (GO:0006278); DNA integration (GO:0015074); negative regulation of viral replication (GO:0045071); pyroptosis (GO:0070269); inflammasome complex assembly (GO:0061702) (moezpoor2024helporhinder pages 22-23, holloway2024inhibitionofcaspase pages 1-2) - GO Cellular Components: plasma membrane (GO:0005886); viral capsid (GO:0019030); pre‑integration complex (GO:0019031); nuclear chromatin (GO:0000785); inflammasome complex (GO:0061702) (moezpoor2024helporhinder pages 22-23, holloway2024inhibitionofcaspase pages 1-2) - CL (cell types): memory CD4+ T cell (CL:0000907); Tfh (CL:0002038); TRM (CL:0000913); macrophage (CL:0000235); microglia (CL:0000129) (armanitourret2024immunetargetingof pages 16-18, castillo2024myeloidcellreservoirs pages 9-10) - UBERON (anatomy): lymph node (UBERON:0000029); germinal center (UBERON:0002367); small intestine (UBERON:0002108); colon (UBERON:0001155); brain (UBERON:0000955) (lau2025hivandthe pages 1-2, armanitourret2024immunetargetingof pages 16-18) - HP (phenotypes): Opportunistic infections (HP:0004322); Lymphopenia (HP:0001888); Decreased CD4+ T cells (HP:0040084); Chronic diarrhea (HP:0002027); Cognitive impairment (HP:0100543) (lau2025hivandthe pages 1-2, holloway2024inhibitionofcaspase pages 1-2, mohammadzadeh2025hivpersistencein pages 37-43)

Notes on limitations and open questions - Some mechanistic areas (e.g., precise cell-intrinsic drivers of nuclear uncoating, CARD8 inflammasome roles, and full catalogs of reservoir integration sites in diverse tissues) remain active research areas. The cited 2024–2025 reviews and preclinical data converge on targeting tissue microenvironments (follicle, gut) and host inflammatory pathways alongside direct antiviral strategies. (armanitourret2024immunetargetingof pages 16-18, holloway2024inhibitionofcaspase pages 1-2, lau2025hivandthe pages 1-2)

Citations (URLs and publication dates embedded above; supporting IDs): (moezpoor2024helporhinder pages 22-23, yildirir2024smacmimeticssensitize pages 24-31, lau2025hivandthe pages 1-2, armanitourret2024immunetargetingof pages 16-18, holloway2024inhibitionofcaspase pages 1-2, mohammadzadeh2025hivpersistencein pages 37-43, yildirir2024smacmimeticssensitize pages 191-196, calado2024decipheringthemechanisms pages 199-203, castillo2024myeloidcellreservoirs pages 9-10, armanitourret2024immunetargetingof pages 20-22)

References

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