HIV
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HIV (Human Immunodeficiency Virus) - Comprehensive Overview
Virology & Classification
HIV belongs to the family Retroviridae, genus Lentivirus. It is a single-stranded, enveloped RNA virus with a genome of ~9.75 kb. Two species exist:
- HIV-1 - responsible for the global pandemic; multiple subtypes (clades), with clade B predominant in developed countries
- HIV-2 - typically produces lower viral loads and slower progression to AIDS; more common in West Africa
HIV infects cells bearing the CD4 receptor (primarily CD4+ T cells, macrophages, and dendritic cells). Entry requires two co-receptors: CCR5 (used by R5-tropic strains, especially during early infection) and CXCR4 (used by X4-tropic strains, associated with later disease). Individuals homozygous for a CCR5 deletion (CCR5Δ32) are largely resistant to HIV-1 infection - a fact exploited in the rare HIV "cures" achieved via CCR5-mutant bone marrow transplantation.
Transmission
- Sexual contact (most common globally) - risk is highest with anal intercourse and highest viral loads
- Blood exposure - sharing needles, transfusions, needle-stick injuries
- Vertical (mother-to-child) - during pregnancy, childbirth, or breastfeeding; maternal viral load is the strongest predictor of perinatal transmission (Lancet 2025)
- Not transmitted by casual contact, saliva, tears, or insect bites
Co-infection with hepatitis B, hepatitis C, and HHV-8 (Kaposi sarcoma herpesvirus) is common given shared transmission routes.
Pathophysiology
Replication Cycle
HIV binds CD4 via its surface glycoprotein gp120, then engages a co-receptor (CCR5 or CXCR4). The transmembrane protein gp41 mediates membrane fusion. After entry, viral reverse transcriptase copies the RNA genome into double-stranded DNA, which integrase inserts into the host chromosome as provirus. The virus then hijacks host machinery to produce new viral particles.
CD4 T Cell Depletion
Progressive destruction and dysfunction of CD4+ T cells is the central immunopathological event. Mechanisms include:
- Direct viral cytopathy
- Immune-mediated killing of infected cells
- Chronic immune activation and inflammation
- Pyroptosis of bystander uninfected CD4+ T cells
As CD4+ counts fall below 200 cells/µL, susceptibility to opportunistic infections rises sharply - this threshold defines the transition from HIV infection to AIDS.
Viral Reservoirs
Even with fully suppressive ART, HIV persists in latently infected resting memory CD4+ T cells and other long-lived cells. This latent reservoir is the principal obstacle to eradication. Forces driving persistence include homeostatic proliferation, antigen-driven expansion, and provirus-driven clonal expansion.
Clinical Stages
1. Acute HIV Infection (Acute Retroviral Syndrome)
- Onset: typically 2-4 weeks after exposure (range up to 10 months)
- Symptoms (mononucleosis/flu-like): fever, lymphadenopathy, pharyngitis, generalized rash (small pink maculopapules, 5-10 mm, appear 48-72 h after fever onset), myalgia/arthralgia, diarrhea, headache (often retroorbital, worsened by eye movement), weight loss
- Viral load peaks at 10^5 to 10^7 copies/mL within ~2 weeks - patients are highly infectious
- CD4 count drops sharply then partially recovers
- 10-40% of acute infections are asymptomatic
- Differential: mononucleosis, toxoplasmosis, rubella, syphilis, viral hepatitis
2. Chronic HIV Infection (Clinical Latency)
- Lasting months to years without ART; patient may be asymptomatic
- Ongoing viral replication and progressive CD4 decline (average ~50-100 cells/µL/year without treatment)
- Persistent generalized lymphadenopathy may be present
- "Elite controllers" (<1% of patients) spontaneously maintain undetectable viremia without ART - linked to HLA-B27 and HLA-B57 alleles - but still have elevated cardiovascular risk from residual inflammation
3. AIDS
Defined by:
- CD4+ T cell count <200 cells/µL, OR
- Presence of an AIDS-defining illness regardless of CD4 count
Key AIDS-defining illnesses include: Pneumocystis jirovecii pneumonia (PCP), CNS toxoplasmosis, CMV retinitis/colitis, cryptococcal meningitis, Mycobacterium avium complex (MAC), Kaposi sarcoma, CNS lymphoma, wasting syndrome, HIV encephalopathy.
Diagnosis
Testing algorithm (CDC/DHHS):
- Combined 4th-generation antigen/antibody immunoassay (detects HIV-1/2 antibodies + HIV-1 p24 antigen) - preferred initial test; detects infection ~18 days after exposure
- Reactive screen → HIV-1/HIV-2 antibody differentiation immunoassay
- If antibody indeterminate or negative but acute HIV suspected → HIV-1 RNA NAAT (viral load)
Key lab values after diagnosis:
| Test | Purpose |
|---|---|
| CD4+ count | Baseline immune status; guides prophylaxis thresholds |
| HIV-1 RNA (viral load) | Baseline; monitor ART response |
| HIV resistance genotype | Before starting ART |
| HLA-B*5701 | Screens for abacavir hypersensitivity |
| Hepatitis B/C serology | Co-infection screening |
| STI screening, TB test | Routine at baseline |
WHO/CDC Staging
CDC Classification:
- Stage 1: CD4 ≥500 cells/µL
- Stage 2: CD4 200-499 cells/µL
- Stage 3 (AIDS): CD4 <200 cells/µL or AIDS-defining condition
Antiretroviral Therapy (ART)
Goal: Achieve undetectable viral load (<20 copies/mL), immune reconstitution, and prevent transmission.
When to start: ART is recommended for ALL people with HIV, regardless of CD4 count. Urgency is greatest with CD4 <200, pregnancy, AIDS-defining illness, HIV-associated nephropathy, or co-infection with hepatitis B.
Drug Classes
| Class | Abbreviation | Mechanism | Examples |
|---|---|---|---|
| Nucleoside/nucleotide reverse transcriptase inhibitors | NRTIs | Competitive inhibition + chain termination of reverse transcriptase | Tenofovir (TDF/TAF), emtricitabine (FTC), lamivudine (3TC), abacavir (ABC), zidovudine (AZT) |
| Non-nucleoside reverse transcriptase inhibitors | NNRTIs | Non-competitive binding to reverse transcriptase | Efavirenz, rilpivirine, doravirine |
| Integrase strand transfer inhibitors | INSTIs | Block viral DNA integration into host genome | Dolutegravir (DTG), bictegravir (BIC), raltegravir (RAL), cabotegravir |
| Protease inhibitors | PIs | Block viral polyprotein cleavage | Darunavir, lopinavir/ritonavir |
| Entry/fusion inhibitors | - | Block viral attachment or fusion | Maraviroc (CCR5 antagonist), enfuvirtide (fusion inhibitor), fostemsavir (CD4 attachment inhibitor) |
| Capsid inhibitor | - | Disrupts capsid function | Lenacapavir (long-acting injectable, every 6 months) |
Preferred Initial Regimens (US DHHS Guidelines)
INSTI-based regimens are preferred:
- Bictegravir/tenofovir alafenamide/emtricitabine (Biktarvy) - single tablet once daily
- Dolutegravir/abacavir/lamivudine (Triumeq) - requires HLA-B*5701 negative
- Dolutegravir + lamivudine (Dovato) - 2-drug regimen; not for HIV RNA >500,000 or HBV co-infection
- Dolutegravir + tenofovir (TAF or TDF) + emtricitabine or lamivudine
INSTIs (especially DTG and BIC) have high barriers to resistance - requiring multiple mutations for resistance to develop.
Drug Resistance
HIV's error-prone reverse transcriptase generates a "swarm" of viral variants. Key resistance mutations:
- M184V in reverse transcriptase → resistance to emtricitabine and lamivudine (single mutation)
- K65R → tenofovir resistance
- Multiple mutations needed for PI and INSTI resistance (DTG, BIC) = high barrier to resistance
Monitoring on ART
- Viral load at 4-8 weeks after ART initiation, then every 3-6 months until undetectable, then every 6-12 months
- CD4 count every 3-6 months until >200; less frequent once stable on ART
- Viral suppression to <200 copies/mL means U = U (Undetectable = Untransmittable) - no sexual transmission risk
Opportunistic Infection Prophylaxis
| CD4 Threshold | Prophylaxis |
|---|---|
| <200 cells/µL | PCP prophylaxis: TMP-SMX (first line) |
| <100 cells/µL | Toxoplasmosis prophylaxis: TMP-SMX |
| <50 cells/µL | MAC prophylaxis: azithromycin weekly |
Immune reconstitution with ART is the most effective method to prevent opportunistic infections; prophylaxis can be safely discontinued once CD4 rises above respective thresholds.
Immune Reconstitution Inflammatory Syndrome (IRIS): Exaggerated immune response to opportunistic infections after ART initiation, especially with CD4 <100 cells/µL. Most common with TB, cryptococcal disease, CMV.
Prevention
| Strategy | Details |
|---|---|
| PrEP (Pre-exposure prophylaxis) | Tenofovir/emtricitabine (Truvada or generic) daily oral; or cabotegravir injections every 2 months; highly effective (>99%) in adherent users |
| PEP (Post-exposure prophylaxis) | Must be started within 72 hours of exposure; tenofovir/emtricitabine + dolutegravir (or raltegravir) for 28 days |
| Condoms | Consistent use reduces transmission by ~80-85% |
| U=U | People with undetectable viral load on ART cannot sexually transmit HIV |
| PMTCT | ART during pregnancy + delivery + infant prophylaxis reduces vertical transmission to <1% |
Special Considerations
- TB co-infection: All HIV patients should be screened for TB. ART initiation timing depends on CD4 count; for CD4 <50, start ART within 2 weeks of TB treatment. Rifampin interactions with ARVs (especially PIs) require regimen adjustments.
- Hepatitis B co-infection: Tenofovir-containing regimens cover both; stopping ART can cause hepatitis B flares.
- CNS disease: HIV-associated dementia, cryptococcal meningitis, CNS toxoplasmosis, PML (JC virus) all occur with advanced disease.
- Malignancies: Kaposi sarcoma (HHV-8), primary CNS lymphoma (EBV), invasive cervical cancer are AIDS-defining. Non-AIDS-defining malignancies (lung, anal, liver) also elevated even on ART.
- Cardiovascular disease: Accelerated atherosclerosis from chronic immune activation remains a concern even with viral suppression.
Towards a Cure
HIV eradication has been achieved in a small number of individuals via bone marrow transplantation from CCR5Δ32 homozygous donors (the "Berlin patient," "London patient," and others). This is not scalable. Active research focuses on:
- "Shock and kill" - latency-reversing agents to flush out reservoirs, then immune clearance
- Gene editing (CRISPR) to excise proviral DNA
- Long-acting therapeutics (e.g., lenacapavir every 6 months)
- Broadly neutralizing antibodies (bNAbs)
Sources:
- Goldman-Cecil Medicine, Chapter 354/355/357 (HIV pathophysiology, acute infection, ART)
- Henry's Clinical Diagnosis and Management by Laboratory Methods (HIV diagnostics)
- Sherris & Ryan's Medical Microbiology (HIV immunosuppression mechanisms)
- Washington Manual of Medical Therapeutics (PEP protocols)
- Recent PubMed evidence: viral load & perinatal transmission, Lancet 2025 | low-level viraemia & virological failure, Emerg Microbes Infect 2025
- CDC/DHHS ART guidelines | WHO HIV recommendations
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