HIV - Etiopathogenesis, Diagnosis, and Management

1. ETIOLOGY

The Virus

• HIV-1 - responsible for the global pandemic; further divided into groups M (major, >90% of cases), O (outlying), N (new), and P.
• HIV-2 - less virulent; prevalent mainly in West Africa; naturally resistant to NNRTIs and enfuvirtide.

Structure

• gp120 - binds CD4 receptor on host cells
• gp41 - mediates membrane fusion after coreceptor binding

Transmission Routes

• Sexual contact (anal > vaginal > oral) - most common globally
• Parenteral - sharing needles/syringes, blood transfusions, needle-stick injuries
• Vertical (mother-to-child) - transplacental, intrapartum, breastfeeding. Maternal viral load is a major determinant of perinatal transmission (Lancet 2025 systematic review, PMID 40652949).

2. PATHOGENESIS

Step-by-Step Life Cycle

1. HIV gp120 binds to CD4 receptor on T-helper cells, macrophages, and dendritic cells.
2. A conformational change exposes the coreceptor binding site.
3. gp120 then binds the CCR5 coreceptor (M-tropic strains, important in early infection) or CXCR4 (T-tropic strains, later disease).
4. gp41 mediates membrane fusion, releasing the viral core into the cytoplasm.

• The viral protein Vif binds and degrades host APOBEC3G (a cytidine deaminase that would otherwise introduce lethal mutations into viral DNA).

Natural History and Stages

Mechanisms of CD4+ T-Cell Depletion

1. Direct cytopathic effect - viral replication leads to cell lysis (primary mechanism in circulating T cells)
2. Syncytium formation - gp120 on infected cells binds CD4 on neighboring uninfected cells, forming giant multinucleated cells
3. Apoptosis - both infected and uninfected bystander T cells undergo programmed death
4. ADCC (Antibody-dependent cell cytotoxicity) - anti-gp120 antibodies on infected CD4+ cell surfaces trigger NK cell-mediated killing
5. Interference with T-cell maturation in the thymus
6. CTL killing of infected cells

Infection of Non-T Cells

• Macrophages - express CCR5 and low-level CD4; >90% of acute infections are by M-tropic (CCR5-using) strains. Macrophages are resistant to HIV cytopathic effects and act as a long-term viral reservoir, especially in the lungs and brain. Infected monocytes carry HIV to the CNS (explaining HIV encephalopathy).
• Dendritic cells - mucosal DCs capture virus and transport it to lymph nodes, facilitating T-cell infection. DC-SIGN (a lectin receptor) binds HIV and presents it to T cells in intact, infectious form.
• Follicular dendritic cells (FDCs) - trap antibody-coated virions on their surface; these retain infectivity for CD4+ follicular helper T cells.

B-Cell Dysfunction

• Hypergammaglobulinemia
• Germinal center hyperplasia
• Autoimmune phenomena (e.g., immune thrombocytopenia)
• Impaired specific antibody responses to new antigens (due to overwhelmed B-cell capacity)

Why HIV Persists Despite Immune Response

• High mutation rate - generates CTL and antibody escape variants
• Latent proviral reservoir - integrated DNA in resting CD4+ memory T cells is invisible to immune surveillance
• Cell-to-cell spread - bypasses neutralizing antibodies
• MHC I and II suppression - impairs antigen presentation
• Antigenic variation - especially in the envelope gene (20-30% inter-clade variation)

3. DIAGNOSIS

HIV Testing Algorithm (2014 CDC Recommended)

• Detects both p24 antigen AND HIV-1/HIV-2 antibodies simultaneously
• HIV can be detected as early as 18 days post-infection
• Sensitivity: 99-100% | Specificity: 98-100%
• Positive result → proceed to Step 2

• Distinguishes HIV-1 from HIV-2 antibodies
• Replaces the old Western blot as the confirmatory test

• If Step 1 reactive but Step 2 negative/indeterminate
• HIV RNA detectable from ~11 days post-infection (earliest detection)
• In acute retroviral syndrome: viral load typically >100,000 copies/mL
• A viral load <10,000 copies/mL on an initial test should raise suspicion for a false positive

Key point: Because the 4th-generation Ag/Ab assay may be negative at the time of acute seroconversion, an HIV viral load assay should always be sent when acute HIV is being considered. - Symptom to Diagnosis, 4th Ed.

Additional Baseline Testing After HIV Diagnosis

CDC Staging (2014 revised)

4. MANAGEMENT

Principle: Treat Everyone

Drug Classes

Note: NNRTIs, enfuvirtide, and fostemsavir are NOT active against HIV-2 and should not be used in HIV-2-infected patients. - Harrison's 22e

Preferred First-Line Regimens (Treatment-Naive Adults)

• Bictegravir/Tenofovir AF/Emtricitabine (Biktarvy) - single-pill, once daily ✓
• Dolutegravir + Tenofovir/Emtricitabine - highly effective, high barrier to resistance ✓
• Dolutegravir + Lamivudine (2-drug regimen) - for HBV-negative patients with baseline HIV RNA <500,000 copies/mL ✓

Monitoring on ART

Opportunistic Infection (OI) Prophylaxis

Post-Exposure Prophylaxis (PEP)

• Indicated within 72 hours of exposure to HIV-infected blood or body fluids (sexual, needlestick, or non-occupational).
• Regimen: Tenofovir-Emtricitabine 300/200 mg once daily + Dolutegravir 50 mg once daily for 28 days.
• Follow-up HIV testing at 6 weeks. - Washington Manual of Medical Therapeutics

Pre-Exposure Prophylaxis (PrEP)

• Oral PrEP: Tenofovir AF/Emtricitabine (Descovy) or Tenofovir DF/Emtricitabine (Truvada)
• Injectable PrEP: Cabotegravir IM every 2 months (highly effective, superior to oral in some trials)
• Indicated for HIV-negative individuals at substantial risk.

Special Populations

• Pregnancy: Continue ART throughout. Prefer dolutegravir-based regimens. Viral load suppression reduces MTCT to <1%. IV Zidovudine during labor if viral load >1000 copies/mL. - Lancet 2025 meta-analysis PMID 40652949
• TB coinfection: Start TB treatment first; introduce ART within 2-8 weeks (within 2 weeks if CD4 <50).
• HIV-2: Avoid NNRTIs, enfuvirtide, fostemsavir; use INSTI-based regimens.

Targets: UNAIDS 95-95-95

HIV - Quick Summary

Etiopathogenesis

• gp120 binds CD4 receptor → then binds coreceptor (CCR5 or CXCR4) → gp41 mediates membrane fusion → viral RNA enters cell
• Reverse transcriptase converts RNA → DNA → integrates into host genome (provirus)
• Slowly destroys CD4+ T cells (~100 billion virions/day; 1-2 billion CD4 cells die daily)
• When CD4 <200/µL → AIDS → opportunistic infections

1. Acute (weeks 2-6): fever, rash, lymphadenopathy, high viremia
2. Latency (years): asymptomatic, CD4 slowly falls
3. AIDS (CD4 <200): OIs, malignancies, death

Diagnosis

Acute HIV → always send viral load (Ag/Ab test can still be negative)

Management

• Bictegravir/TAF/FTC (Biktarvy) - single pill once daily
• Dolutegravir + TDF/FTC - widely used globally

• CD4 <200 → TMP-SMX (PCP)
• CD4 <50 → Azithromycin (MAC)