HIV / AIDS

Overview

• Harrison's Principles of Internal Medicine 22E, p. 1015

The Virus

Pathogenesis

Fig. 6.41 Pathogenesis of HIV-1 infection - Robbins Pathologic Basis of Disease

• HIV gains entry via mucosal surfaces (genital, rectal, oral) or direct bloodstream inoculation
• gp120 binds CD4 and a co-receptor (CCR5 on macrophages/memory T cells; CXCR4 on naive T cells)
• Dendritic cells at the mucosa capture virus and transport it to regional lymph nodes
• Massive destruction of memory CD4+ T cells occurs in mucosal lymphoid tissue within days - this is the largest reservoir of memory T cells in the body

1. Direct lytic infection - virus replication kills infected cells
2. Activation-induced cell death (apoptosis) - chronic activation of uninfected bystander cells
3. Pyroptosis - abortive HIV infection activates the inflammasome, triggering inflammatory cell death and recruiting more susceptible cells
4. Syncytium formation - gp120 on infected cells binds CD4 on uninfected cells, causing fusion and death (T-tropic X4 HIV-1)
5. Lymphoid tissue destruction - progressive damage to lymph node architecture
6. Reduced thymic output - infection of progenitor cells reduces CD4+ T cell production

Clinical Stages and Natural History

Fig. 6.42 Clinical course of HIV infection showing inverse relationship between CD4+ count and viremia - Robbins

Stage 1 - Acute HIV Syndrome (weeks 2-4)

• Occurs in ~50-70% of newly infected individuals
• Resembles infectious mononucleosis: fever, lymphadenopathy, pharyngitis, rash, myalgias, headache
• Extremely high viremia (>10^6 copies/mL), with sharp transient drop in CD4 count
• Host mounts CTL and humoral response, partially controlling viremia

Stage 2 - Clinical Latency (months to ~10 years)

• Patient is often asymptomatic
• Viral replication continues at low level; CD4+ count falls gradually (~50-100 cells/μL per year)
• Generalized lymphadenopathy may occur
• Patient remains infectious throughout

Stage 3 - AIDS

• CD4+ count <200 cells/μL (in adults/adolescents ≥6 years), OR
• Presence of an AIDS-defining opportunistic illness (Stage C)

CDC Classification

AIDS-Defining Opportunistic Illnesses

Infections

Neoplasms

• Kaposi's sarcoma (HHV-8 driven; violaceous skin/mucosal lesions)
• Primary CNS lymphoma
• Burkitt's/immunoblastic lymphoma
• Invasive cervical cancer

Key clinical pearls:

• Oral candidiasis in an HIV+ patient signals immune decompensation and often heralds the transition to AIDS
• CMV retinitis occurs almost exclusively when CD4 <50 cells/μL
• MAC infection is a late complication (CD4 <50); TB can occur much earlier
• Worldwide, ~1/3 of AIDS deaths are attributable to tuberculosis

Abnormalities of Immune Function in AIDS

Diagnosis

Antiretroviral Therapy (ART)

Drug Classes

Standard Regimen

Opportunistic Infection Prophylaxis (CD4-based thresholds)

Prevention

• Pre-exposure prophylaxis (PrEP): Daily oral tenofovir/emtricitabine or long-acting injectable cabotegravir (every 2 months) for HIV-negative high-risk individuals. Highly effective (>99% when taken consistently).
• Post-exposure prophylaxis (PEP): 3-drug ART started within 72 hours of exposure, continued for 28 days.
• Undetectable = Untransmittable (U=U): People with sustained undetectable viral load cannot sexually transmit HIV.
• PMTCT: Prevention of mother-to-child transmission via maternal ART + infant prophylaxis reduces transmission to <1%.

Ethical and Legal Dimensions

• HIV testing requires pre-test and post-test counselling; results must be delivered face-to-face, not by phone or third party
• Mandatory testing (without individual consent) is permitted only for screening blood/organ/tissue donors
• HIV-positive healthcare workers cannot be removed from service if physically capable of performing duties (with appropriate precautions for exposure-prone procedures)
• WHO states there is no public health rationale for isolation, quarantine, or discrimination based on HIV status

Current Evidence (2024-2026)

• Low-level viraemia (detectable but <200 copies/mL) is associated with increased risk of virological failure and warrants close monitoring - Zaçe et al., 2024 (PMID 39288983)
• Prevalence of low-level viraemia and its link to virological failure is well-characterized - Zhao et al., 2025 (PMID 39727007)
• Maternal viral load is the dominant driver of perinatal HIV transmission - Dugdale et al., 2025 Lancet (PMID 40652949)

Summary at a Glance

HIV (RNA retrovirus)
  ↓ binds CD4 + CCR5/CXCR4
  ↓ integrates as provirus
  ↓ progressive CD4+ T cell loss
  ↓ CD4 <200 OR AIDS-defining illness
  = AIDS
     ↓
Opportunistic infections + Malignancies
     ↓ (without ART)
Death