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- Virus: ssRNA retrovirus, Lentivirus genus, Retroviridae family
- 2 types: HIV-1 (worldwide main) + HIV-2 (W Africa, milder course)
- HIV-1 Subtypes: M (main, ~ 90%; subtypes A, B, C, D, F, G, H, J, K; recombinants); O (Cameroon); N (rare); P
- Origin: SIV from chimpanzees + SIV cpz â HIV-1 (multiple cross-species events ~ 1920s Congo)
- Receptor: CD4 + co-receptor (CCR5 or CXCR4)
- Target cells: CD4+ T cells, monocytes/macrophages, dendritic cells, microglia
- Transmission:
- Sexual (heterosexual + homosexual) â most common globally
- Blood (IDU, transfusion, healthcare exposures)
- Vertical (in utero, intrapartum, breastfeeding)
- Stages:
- Acute HIV (Weeks 1-4): mononucleosis-like syndrome (fever + LAP + rash + pharyngitis); ~ 50% symptomatic; high viral load
- Clinical latency (Years): gradual CD4 decline (~ 50-80 cells/µL/yr untreated)
- AIDS (CD4 < 200 or AIDS-defining illness): opportunistic infections + malignancies
- Global Stats (UNAIDS 2023):
- 39M people living with HIV
- 1.3M new infections/yr
- 630K AIDS deaths/yr
- Sub-Saharan Africa highest burden
- 76% diagnosed, 71% on ART, 67% virally suppressed (2023; goal 95/95/95 by 2030)
- Pathogenesis:
- HIV binds CD4 + co-receptor â entry
- Reverse transcription â integrate into host genome (latency)
- Productive infection â CD4 destruction (direct + immune-mediated)
- Chronic immune activation + inflammation
- Eventual immune collapse
- Acute Retroviral Syndrome (ARS):
- Mononucleosis-like: fever, fatigue, LAP (especially cervical), maculopapular rash, pharyngitis, myalgia, headache, weight loss
- Sometimes oral / genital ulcers
- Sometimes encephalitis, meningitis
- 2-4 wk after exposure
- Many missed because mild / atypical
- Diagnosis:
- Antibody/antigen test (4th-gen combo): HIV antibody + p24 antigen
- HIV RNA PCR for acute infection (before seroconversion)
- Confirmatory: HIV-1/HIV-2 differentiation assay
- U=U (Undetectable = Untransmittable):
- Sustained viral load < 200 copies/mL on ART = no sexual transmission
- PARTNER + PARTNER2 + Opposites Attract trials = no transmissions documented
- Major messaging revolution
1ïžâ£ Virology
Structure
- ~ 100 nm enveloped
- Diploid ssRNA genome
- Gp120 (surface) + Gp41 (transmembrane) â envelope glycoproteins
- p24 (capsid)
- p17 (matrix)
- Reverse transcriptase, integrase, protease enzymes
Genome (~ 9.7 kb)
- gag (capsid + matrix + nucleocapsid)
- pol (RT + integrase + protease)
- env (gp120 + gp41)
- 6 regulatory genes: tat, rev, nef, vif, vpr, vpu/vpx
Lifecycle
- Entry: gp120 â CD4 receptor + co-receptor (CCR5 or CXCR4) â conformational change â gp41-mediated fusion
- Reverse transcription (RT): RNA â cDNA (error-prone, source of mutations)
- Integration: integrase incorporates proviral DNA into host genome
- Transcription: host RNA Pol II reads provirus
- Translation + Processing: viral proteins + RNA
- Assembly + Budding: at cell membrane
- Maturation: protease cleaves Gag/Gag-Pol polyprotein
Drug Targets (See Ch 217 in detail)
- Entry inhibitors: maraviroc (CCR5), enfuvirtide (gp41 fusion), ibalizumab (CD4 attachment), fostemsavir (gp120 attachment)
- NRTIs/NtRTIs: reverse transcriptase nucleoside/nucleotide analogs (TDF, TAF, FTC, ABC, etc.)
- NNRTIs: non-nucleoside RT inhibitors (efavirenz, rilpivirine, doravirine)
- Integrase strand transfer inhibitors (INSTIs): dolutegravir, bictegravir, raltegravir, cabotegravir
- Protease inhibitors (PIs): darunavir, atazanavir (often boosted with cobicistat or ritonavir)
- Capsid inhibitors: lenacapavir (long-acting)
Viral Diversity + Mutations
- HIV-1 mutation rate ~ 10^-4 per base per replication cycle
- Quasispecies (heterogeneous viral population within infected individual)
- Pre-existing drug resistance mutations â consider in initial regimen
- Resistance testing routine in modern HIV care
HIV-2
- Endemic W Africa
- Slower progression
- Naturally resistant to NNRTIs (efavirenz doesnât work)
- äžå ART regimen + monitoring (no HIV-2 RNA assay routine)
- Vertical + sexual transmission
2ïžâ£ Epidemiology
Global
- 39 million living with HIV (UNAIDS 2023)
- 1.3 million new infections/year
- 630,000 AIDS deaths/year (down from 2.1M peak 2004)
Regional Distribution
- Sub-Saharan Africa: 25M (66%); women + adolescent girls disproportionate
- Asia + Pacific: ~ 6M (esp Thailand, India, Indonesia, Vietnam, Philippines)
- Latin America + Caribbean: ~ 2.5M
- Eastern Europe + Central Asia: ~ 1.7M (rising with IDU)
- Western + Central Europe + North America: 2.1M
- MENA: 200K
Demographics
Sub-Saharan Africa
- Heterosexual transmission predominant
- Women + adolescent girls (60% new infections)
- Economic + social drivers
USA + Europe
- MSM + transgender highest incidence (60% new infections USA)
- IDU outbreaks (West Virginia, Indiana)
- Heterosexual + women secondary
- Disproportionate Black + Latinx populations
Asia
- MSM, IDU, sex worker primarily
- Heterosexual rising
Key Populations
- MSM, transgender women, sex workers, IDU, prisoners â disproportionate risk
- 80%+ of new infections in key populations globally
Progress 95-95-95
- 2023 status: 86-89-93 globally (varies by region)
- 2030 target: 95% diagnosed, 95% on ART, 95% virally suppressed
- Some countries achieved (Australia, Denmark, Sweden, Switzerland)
- Sub-Saharan Africa improving rapidly
2024 Trends
- New infections declining (since 2010 peak)
- AIDS deaths declining
- Persistent inequalities (geographic, demographic, key populations)
- Funding pressures (PEPFAR, Global Fund)
3ïžâ£ Pathogenesis
Acute Infection (Weeks 1-4)
- HIV enters mucosa â local dendritic cells â lymph nodes â systemic dissemination
- Massive viral replication
- Peak viremia 106-107 copies/mL
- CD4 transient drop (50% may have ARS)
- Antibody response (seroconversion) by 4-8 weeks
Acute Retroviral Syndrome (ARS)
- ~ 50% have symptomatic ARS (many missed)
- 2-4 weeks post-exposure
- Mononucleosis-like:
- Fever (96%)
- Fatigue (74%)
- Generalized LAP (especially cervical, axillary, occipital)
- Maculopapular rash (often trunk + face)
- Pharyngitis
- Myalgia
- Headache
- Sometimes:
- Oral / genital ulcers
- Meningitis / meningoencephalitis
- GBS-like
- Hepatitis
- Self-limited 2-4 weeks
Set Point + Clinical Latency
- Viral load decreases to âset pointâ after acute (predictor of disease progression)
- Higher set point = faster progression
- Continued CD4 decline ~ 50-80 cells/year on average
Latency Reservoirs
- Resting memory CD4+ T cells: major reservoir for cccDNA-equivalent (integrated provirus)
- Macrophages, microglia, follicular dendritic cells
- Anatomic sites: lymph node germinal centers, brain, GI tract, genital tract
- Persistence of reservoir = primary obstacle to cure
Immune Activation
- Chronic immune activation drives morbidity (beyond CD4 decline)
- Inflammation â CVD + neuro + metabolic
- Contributes to non-AIDS complications
Progression to AIDS
- CD4 < 200/µL OR AIDS-defining illness
- WHO clinical stages (1-4)
- US CDC stages (A1-C3)
- Without ART: ~ 10 yr median to AIDS, then ~ 2 yr to death
- With ART: near-normal life expectancy in well-managed patients
4ïžâ£ Transmission
Sexual
- Receptive anal: highest risk (~ 1.4% per act unprotected)
- Insertive anal: ~ 0.1% per act
- Receptive vaginal: ~ 0.08% per act
- Insertive vaginal: ~ 0.04% per act
- Oral sex: low risk but possible
- Concurrent STDs (especially ulcerative â syphilis, HSV, chancroid) increase transmission
- Viral load critical â undetectable = no transmission
Blood
- IDU sharing: ~ 0.6% per exposure
- Transfusion (pre-screening era): very high; now < 1/2M units
- Healthcare needlestick: 0.3% per exposure (lower with PEP)
Vertical
- In utero: 5%
- Intrapartum: 15%
- Breastfeeding: 15% over duration
- Without prevention: ~ 25-30% total
- With maternal ART + cesarean if needed + formula feeding: < 2%
- 2024 WHO recommendations: maternal ART for all pregnant HIV+, infant prophylaxis post-delivery
Risk Modifiers
- Viral load (most important â undetectable = no transmission for sexual)
- Concurrent STDs (especially ulcers)
- Genital inflammation
- Sex during menstruation
- Trauma
- Lack of circumcision (slightly higher risk for male partner)
U=U (Undetectable = Untransmittable)
- 2016+ established by major trials:
- PARTNER (2016): 0 transmissions in 1238 couple-years
- PARTNER2 (2018): 0 transmissions in 1593 couple-years (MSM)
- Opposites Attract (2018): 0 transmissions in 358 couple-years
- Suppressed HIV viral load < 200 copies/mL = no sexual transmission
- Major public health + patient empowerment messaging
- Reduces stigma + criminalization concerns
5ïžâ£ Diagnosis
Screening Tests
4th-Generation Combo Test (Antigen/Antibody)
- HIV-1 + HIV-2 antibody + HIV-1 p24 antigen
- Window period reduced to ~ 2-3 weeks post-exposure (vs 3-6 wk for Ab alone)
- Standard initial screening
Rapid HIV Tests
- Point-of-care 15-30 min
- Antibody only (some 4th-gen)
- For acute setting, screening, self-test
Confirmatory
HIV-1/HIV-2 Differentiation Assay
- After positive screen
- Distinguishes HIV-1 from HIV-2
- Western blot replaced by multispot assays
HIV RNA PCR (Quantitative)
- Useful for:
- Acute HIV (before antibody)
- Pediatric < 18 mo (maternal Ab interferes)
- Indeterminate or confirmed
- Quantitative for viral load monitoring on ART
Window Periods
- HIV RNA PCR: detectable 1-2 wk post-exposure
- p24 antigen: 2-3 wk
- IgM antibody: 3-4 wk
- IgG antibody (full seroconversion): 4-8 wk
- 99% seroconvert by 12 weeks
Acute HIV Workup
- High clinical suspicion (mono-like + risk factor)
- 4th-gen combo: may be positive (p24)
- HIV RNA PCR: positive
- Rapid antibody: negative early
Universal Screening Recommendations
- CDC + USPSTF: routine HIV screening for all 13-64 yr at least once
- High-risk: annual or more frequent
- Pregnant women: 1st prenatal visit + 3rd trimester
- All hospital admissions / ED visits in some regions
Confirmatory Workflow
- 4th-gen combo: + â next step
- HIV-1/HIV-2 differentiation: + â diagnosis
- If differentiation -: HIV RNA PCR (rule out acute, false +)