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HIV / AIDS — Complete Overview

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1. What Is HIV?

• HIV-1 — responsible for the global pandemic; four groups (M, N, O, P), with Group M divided into 11 subtypes/clades (A–K)
• HIV-2 — less virulent, primarily in West Africa; lacks the vpu gene, has a vpx gene instead

• CD4+ T cell count < 200 cells/μL, OR
• Diagnosis of one or more AIDS-defining opportunistic illnesses (CDC Stage C/Stage 3)

"HIV disease is a spectrum ranging from primary infection… to the relatively asymptomatic stage, to advanced stages associated with opportunistic diseases." — Harrison's Principles of Internal Medicine 22E

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2. Virology & Structure

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3. Epidemiology

• ~39 million people worldwide living with HIV (2022)
• ~630,000 deaths attributed to HIV/AIDS in 2022
• ~67% of all cases in Sub-Saharan Africa
• ~50,000 new infections per year in the United States
• ~50% of HIV-infected persons worldwide are unaware of their infection
• Disproportionately affects African Americans, Hispanics/Latinos in the US

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4. Transmission

• High plasma viral load (strongest predictor)
• Presence of genital ulcer disease
• Uncircumcised male
• Concurrent STIs (chlamydia, gonorrhea, trichomoniasis)

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5. Pathogenesis

Primary Target Cells

• CD4+ T lymphocytes (especially memory T cells)
• Monocytes and macrophages
• Dendritic cells (DCs) and Langerhans cells
• Microglial cells (CNS)

How HIV Enters Cells

1. gp120 binds to the CD4 receptor on the host cell surface
2. Co-receptor binding occurs — either CCR5 (M-tropic/R5 virus, early infection) or CXCR4 (T-tropic/X4 virus, late disease)
3. gp41 mediates membrane fusion, allowing viral core entry
4. Reverse transcriptase converts viral RNA → double-stranded DNA
5. Integrase inserts proviral DNA permanently into the host genome

CCR5-Δ32 mutation: Individuals homozygous for this mutation lack surface CCR5 and are resistant to HIV infection (~1% of northern Europeans). CCR5 is the target of the drug maraviroc.

Mechanisms of CD4+ T Cell Destruction

• Direct lytic infection — virus kills activated permissive CD4 T cells
• Apoptosis — induced in non-permissive bystander cells
• Syncytia formation — gp120 on infected cells binds CD4 on uninfected cells → giant cells that die within hours (mainly X4 virus)
• CTL-mediated killing — HIV-specific CD8+ T cells destroy infected cells
• Latent reservoir — integrated provirus in long-lived memory CD4 T cells and germinal center follicular helper T cells persists indefinitely despite ART

Consequences of CD4 Depletion

• Loss of Th1-type cell-mediated immunity → susceptibility to intracellular organisms
• Loss of T-cell help for B cells → impaired humoral responses to new antigens
• Macrophage dysfunction → decreased phagocytosis and antigen presentation
• Gut CD4 T cell depletion → disruption of mucosal barrier → microbial translocation, diarrhea

CNS Involvement (HAND)

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6. Natural History & Clinical Stages

Phase 1: Acute Retroviral Syndrome (weeks 1–6)

• High-level viremia with rapid dissemination to lymphoid tissue
• Occurs in 40–90% of patients
• Presents as: flu-like illness, maculopapular rash, fever, lymphadenopathy, pharyngitis, myalgia, aseptic meningitis, or heterophile-negative mononucleosis-like syndrome
• CD4 count drops sharply, then partially recovers
• Host immune response (CTLs + antibodies) partially controls viremia → viral "set point" established

Phase 2: Clinical Latency (months to years)

• Usually asymptomatic but fully infectious
• CD4 count gradually declines (~50–100 cells/μL per year without ART)
• Viral load stable at set point
• Duration: median ~10 years (range: months to >15 years)
• Later: constitutional symptoms — night sweats, weight loss, fatigue, generalized lymphadenopathy

Phase 3: AIDS (CD4 < 200 cells/μL or AIDS-defining illness)

• Severe immunosuppression → opportunistic infections and tumors

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7. AIDS-Defining Conditions (CDC Stage C / Stage 3)

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8. Diagnosis

Screening

• 4th-generation HIV Ag/Ab immunoassay (recommended): detects both p24 antigen and HIV antibodies; window period ~6–7 days post-infection
• Rapid tests: results in < 20 minutes; CLIA-waived
• Viral load (HIV RNA PCR): used to detect acute infection before seroconversion; required for monitoring

CDC Recommended Testing

• STDs
• Constitutional symptoms (fever, night sweats, weight loss)
• Oral thrush (oropharyngeal candidiasis)
• Herpes zoster in persons < 50 years
• Asymptomatic generalized lymphadenopathy
• Oral hairy leukoplakia

Staging by CD4 Count (Adults ≥ 6 years)

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9. Antiretroviral Therapy (ART)

Drug Classes

Standard Regimen

Long-Acting Injectable ART

Goals of ART

• Suppress viral load to < 20 copies/mL (undetectable)
• Restore and preserve CD4+ T cell counts
• Prevent opportunistic infections and AIDS-defining events
• Prevent transmission (U=U)
• Approach near-normal life expectancy

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10. Immune Abnormalities in AIDS

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11. Opportunistic Infection Prophylaxis

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12. Prevention

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13. Prognosis

• Without ART: median survival from AIDS diagnosis ~2–3 years
• With modern ART: life expectancy approaches that of HIV-negative individuals
• Success with ART exceeds outcomes for most adult cancers or complications of coronary artery disease
• UNAIDS "95-95-95" target (by 2030): 95% know their status → 95% on ART → 95% virally suppressed

"ART transformed HIV infection from an inescapably fatal disease into a manageable chronic illness." — Harrison's Principles of Internal Medicine 22E (2025)

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• Harrison's Principles of Internal Medicine 22E (2025, McGraw-Hill)
• Robbins & Kumar Pathologic Basis of Disease (Elsevier)
• Medical Microbiology 9e (Murray et al.)
• Textbook of Family Medicine 9e