Comprehensive tracking of HIV therapeutic vaccine development for people living with HIV, targeting functional cure (ART-free viral remission). HIV affects 39 million globally (1.2 million US), controlled by antiretroviral therapy (ART) but NOT cured - lifelong daily medication required. HIV establishes latent reservoirs in CD4+ T cells (primarily resting memory T cells) that persist despite ART, viral DNA integrated into host genome dormant but reactivation-competent. Stop ART โ viral rebound within 2-4 weeks from reservoir reactivation. Therapeutic vaccines aim to: (1) "Kick" - reverse latency forcing virus expression, (2) "Kill" - boost HIV-specific immunity eliminating reactivated infected cells, achieving functional cure (virus remains but immune control prevents replication without ART). Leading strategies: Therapeutic vaccines + latency reversal agents (LRAs), broadly neutralizing antibodies (bnAbs), mosaic vaccines, dendritic cell vaccines. Only 2 proven cures: Timothy Ray Brown (Berlin Patient), Adam Castillejo (London Patient) - both via stem cell transplants from CCR5ฮ32 donors (not scalable). Goal: Scalable functional cure 70%+ achieving ART-free remission years. Complementary to antiretroviral therapy and HIV management.
HIV affects 39 million people globally (1.2 million US, 1.7 million children worldwide), 38 million on antiretroviral therapy (ART). Modern ART revolutionized HIV from death sentence to chronic manageable disease - life expectancy near-normal (70+ years), viral suppression achieves "undetectable = untransmittable" (U=U, cannot transmit sexually). However ART does NOT cure: (1) Lifelong daily medication required (1-3 pills/day, cost $20,000-40,000/year US, $100-300/year generic developing countries with subsidies), (2) Side effects - GI upset, fatigue, bone loss, cardiovascular risk, neuropsychiatric effects, kidney/liver toxicity (varies by regimen), (3) Adherence challenges - 95%+ adherence needed, missed doses โ resistance, stigma/disclosure issues, (4) Drug-drug interactions complicating other medical care, (5) Long-term toxicities uncertain (decades of ART). Latent HIV reservoir problem: Virus integrated into host CD4+ T-cell DNA (primarily resting memory T cells, also tissue macrophages, microglia), estimated 1 million latently infected cells per person on suppressive ART, reservoir half-life 44 months (4+ years) - would take 70+ years to naturally decay even on perfect ART, cells long-lived memory T cells (decades lifespan). Stop ART โ viral rebound 50% patients within 2 weeks, 90% within 4 weeks from reservoir reactivation (latent provirus transcribes โ virion production โ infects new cells โ exponential replication). Only 2 HIV cures documented: Timothy Ray Brown ("Berlin Patient" 2008) and Adam Castillejo ("London Patient" 2019) - both underwent myeloablative chemotherapy + allogeneic stem cell transplant from CCR5ฮ32/ฮ32 homozygous donors for cancer treatment (leukemia), CCR5ฮ32 mutation (1% European ancestry) makes cells resistant to R5-tropic HIV (CCR5 co-receptor absent), stem cells reconstituted HIV-resistant immune system, reservoir cleared (combination myeloablation killing infected cells + graft-vs-host eliminating residual reservoir), ART-free >15 years (Brown), >5 years (Castillejo), no viral rebound. Not scalable: Requires matching CCR5ฮ32 donor (rare), dangerous procedure (30% mortality risk myeloablation + transplant), only justified for life-threatening cancer not HIV alone. Functional cure goal: Achieve sustained ART-free viral remission without stem cell transplant - virus remains latent but immune control prevents reactivation/replication, quality of life restoration, eliminate daily medication burden/costs/toxicities.
๐ View all HIV therapeutic vaccine trials on ClinicalTrials.gov โ
๐ UNAIDS - Global HIV Statistics โ
๐ NIH/NIAID HIV Cure Research โ
๐ defeatHIV Collaboratory โ
๐ฐ Latest HIV Cure News (Google) โ
Most promising functional cure strategy
Multi-clade coverage targeting global diversity
Novel therapeutic strategies
Early clinical testing
Next-generation technologies
What is Latent HIV Reservoir? HIV integrates into host CD4+ T-cell chromosomal DNA as provirus. In activated T cells (during acute infection), provirus transcribed โ viral proteins โ virion assembly โ infection spreads. However subset of infected cells transition to resting memory state BEFORE producing virus - provirus remains integrated but transcriptionally silent (no viral RNA/protein production). These latently infected resting memory CD4+ T cells: Invisible to immune system (no viral antigens expressed), not killed by ART (ART blocks new infection and viral replication, doesn't touch integrated proviral DNA), long-lived (memory T cells decades lifespan), reactivation-competent (if cell activated โ provirus transcribes โ virus production โ reinfection cycle resumes). Anatomical sites: Blood (10-20%), lymph nodes (40-60%, major reservoir), gut-associated lymphoid tissue GALT (20-30%), CNS (microglia harbor virus - sanctuary site), genital tract, bone marrow. Cell types: Primarily resting memory CD4+ T cells (central memory TCM, transitional memory TTM), also tissue-resident memory, macrophages (especially CNS microglia - different reservoir characteristics).
Reservoir Size & Dynamics: On suppressive ART, estimated 1 million latently infected cells per person (range 10,000 to 10 million - high variability). Only 1-10% reservoir is replication-competent (produces infectious virus if reactivated), rest defective proviruses (deletions, mutations) but contribute to immune activation. Reservoir half-life 44 months (3.7 years) - extraordinarily stable, would take 70+ years of perfect ART to decay to zero naturally (not feasible). Drivers of reservoir stability: Memory T-cell longevity (decades), homeostatic proliferation (cells divide maintaining pool size - clonal expansion, TCR-driven proliferation in response to antigens), integration sites (proviruses in actively transcribed genes may drive proliferation). Challenge: Even if 99.9% reservoir eliminated, remaining 0.1% (1,000 cells) sufficient for viral rebound - need near-complete clearance for functional cure.
Modern ART Regimens: Highly effective - single tablet once-daily regimens (bictegravir/TAF/FTC, dolutegravir/3TC), viral suppression <50 copies/mL achievable >95% adherent patients within 6 months, U=U (Undetectable = Untransmittable) - suppressed viral load eliminates sexual transmission risk (revolutionary for prevention), life expectancy HIV+ person on ART approaches HIV-negative with early treatment. Classes: NRTIs (nucleoside reverse transcriptase inhibitors - backbone), NNRTIs (non-nucleoside RTIs), PIs (protease inhibitors), INSTIs (integrase strand transfer inhibitors - newest, most potent/tolerable), entry inhibitors (rare - maraviroc CCR5 antagonist).
Why ART Not Cure - Limitations: (1) Lifelong medication - daily pills forever, adherence burden (travel, disclosure, routine), must be taken 95%+ time (missing doses โ resistance risk); (2) Cost - $20,000-40,000/year US without insurance (generic $100-300/year developing countries with subsidies but access barriers), insurance coverage issues; (3) Side effects - vary by regimen: GI upset common (diarrhea, nausea especially PIs), CNS effects (dolutegravir - insomnia, depression, anxiety 10-20%), bone density loss (TDF-based regimens), cardiovascular disease (chronic inflammation despite suppression, some ART contribution), kidney/liver toxicity, weight gain (INSTIs especially - 5-10 lbs average, metabolic effects), lipodystrophy (fat redistribution - older regimens); (4) Drug interactions - many ART drugs CYP450 interactions complicating other medications (statins, antifungals, PPIs, rifampin TB treatment); (5) Resistance - if adherence poor โ viral replication with drug pressure โ resistance mutations, limits future options (though INSTIs high barrier to resistance); (6) Inflammation - chronic immune activation persists despite viral suppression (microbial translocation, persistent low-level viral replication sanctuary sites?), drives comorbidities (cardiovascular disease, cancer, neurocognitive decline); (7) Stigma - lifelong HIV diagnosis, disclosure challenges (dating, employment), internalized stigma mental health; (8) Long-term unknowns - people now living decades on ART, very long-term toxicities (40-50+ years) unknown, aging with HIV accelerated (cardiovascular events, cancers 10-15 years earlier than HIV-negative).
Functional Cure vs. Sterilizing Cure: Sterilizing cure - complete elimination of all HIV DNA from body, no virus remains, theoretically impossible (need eradicate every single infected cell - millions cells scattered throughout body including CNS). Functional cure (remission) - HIV DNA remains latent but immune system controls virus preventing reactivation/replication without ART, no viral load rebound off ART, no disease progression, no transmission, similar to herpesviruses (HSV, CMV, EBV - latent but immune-controlled). Functional cure acceptable goal - achieves all clinical benefits (ART-free, healthy, non-transmissible) without requiring impossible sterilizing cure.
Success Criteria: Consensus definition emerging: (1) Sustained viral suppression (<50 copies/mL) off ART for โฅ12 months (some propose 24+ months), (2) No AIDS-defining illness, (3) Stable/rising CD4+ count, (4) No HIV-specific treatment required. Measured by: Analytical treatment interruption (ATI) - structured ART cessation under close monitoring (viral load every 1-2 weeks, restart ART if rebound >1,000-10,000 copies/mL or CD4 decline), time to viral rebound, magnitude of rebound, reservoir size reduction (cell-associated HIV DNA/RNA).
Post-Treatment Controllers: Rare individuals (<5% HIV+ stopping ART) who naturally control HIV replication without treatment - viral load remains undetectable/very low off ART for years. Not truly "cured" (reservoir persists, can rebound) but functional cure achieved. Mechanisms: Robust HIV-specific T-cell responses, bnAb development, reservoir restricted to defective proviruses, HLA genetics (protective alleles B*27, B*57), low reservoir size at ART initiation (early treatment). Study: French ANRS VISCONTI cohort - 14 patients treated very early acute infection (weeks post-infection), stopped ART after 3 years median, 70% maintained virologic control >5 years off ART, mechanisms: Early ART limited reservoir seeding (<100 infected cells vs. 1 million typical), preserved HIV-specific immunity. Lesson: Early ART initiation (within weeks-months infection) dramatically increases functional cure odds - drives "test and treat" urgency.
Challenges: Reservoir persistence - most stable latent reservoir of any chronic infection. Anatomical sanctuaries (CNS, genital tract - limited ART/immune penetration). Reservoir diversity - millions proviruses, extensive mutations, immune escape variants. Immune exhaustion - decades HIV infection exhausts HIV-specific T cells (PD-1, CTLA-4, LAG-3 upregulation โ anergy). Balancing act - LRAs induce immune activation (inflammation, cytokine release) risky especially in older individuals. Individual variability - reservoir size varies 10,000-fold, HLA genetics, treatment history, co-infections. Safety paramount - any cure strategy must be safer than current ART (ART low toxicity modern regimens, very effective). Scalability - cure must be accessible globally (not stem cell transplant $1M+ and risky). Ethics of ATI - treatment interruptions risky (rebound can be rapid, high viral load, transmission risk, CD4 decline), require close monitoring, informed consent.
Near-Term (2025-2030): Optimization of kick-and-kill combinations - identify best LRA + bnAb + therapeutic vaccine combinations, Phase 2b/3 trials enrolling hundreds patients. First functional cure demonstrated in larger cohort (current trials 10-30 patients, need 100+). mRNA therapeutic vaccines enter Phase 2 combined with LRAs/bnAbs. Long-acting bnAbs (every 6 months injection) replace monthly infusions improving feasibility. Gene therapy approaches (AAV-bnAbs, CRISPR excision) Phase 2 trials. Biomarkers predicting cure success identified (reservoir size, immune parameters) allowing enrichment strategies.
Mid-Term (2030-2040): First therapeutic vaccine or combination therapy approved achieving functional cure 30-50% patients (ART-free remission 12+ months). Functional cure becomes standard treatment option (not universal but available). Combination: therapeutic vaccine + long-acting bnAb + improved LRA + checkpoint inhibitor = 50-70% functional cure rate. Preventive functional cure - vaccinate acute HIV infection patients (before reservoir established) โ 70-80% never need ART. Gene editing (CCR5 knockout, HIV excision) safe/effective 50%+. Post-treatment controllers increase from <5% to 30-50% with interventions.
Long-Term Vision (2040+): Functional cure achievable 70-80% HIV+ patients stopping ART, durable remission (5+ years) majority, rare viral rebound managed with short ART courses re-suppressing. "Cure" redefined - not elimination (sterile cure) but sustained remission (functional cure) acceptable goal achieved. Sterilizing cure small percentage (~10%) via intensive combinations (multiple bnAbs, multiple LRAs, therapeutic vaccine, gene therapy). Prevention + early treatment near-eliminate HIV - test and treat at acute infection, pre-exposure prophylaxis (PrEP) widespread, new infections <10,000 globally/year (vs. 1.5 million current). AIDS-free generation realized - HIV becomes rare, managed infection, stigma eliminated. Lifelong ART rarity not norm - most achieving functional cure. Vision: HIV transitions from chronic lifelong disease requiring daily medication to acute infection treated acutely (weeks-months early ART) followed by immune control (no ongoing treatment) similar to hepatitis C cure with DAAs.