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HIV/AIDS - Clinical & Exam-Focused Guide

1. Virology - The Virus Itself

• Family: Retroviridae, Genus: Lentivirus
• Enveloped, (+) single-stranded RNA virus (diploid genome - carries 2 copies)
• Two types: HIV-1 (global, more virulent) and HIV-2 (West Africa, less pathogenic, lower transmission)

• Goldman-Cecil Medicine 22e, p. 3687

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2. Replication Cycle (Step-by-Step)

1. Attachment: gp120 binds CD4 receptor on T-helper cells/macrophages
2. Co-receptor binding: gp120 then binds CCR5 (macrophage-tropic, M-tropic; early infection) or CXCR4 (T-cell-tropic; late infection) - critical step for membrane fusion
3. Fusion: gp41 mediates fusion of viral and cell membranes - target of fusion inhibitors (enfuvirtide)
4. Reverse transcription: RT converts viral RNA → double-stranded DNA (error-prone → generates high genetic diversity and resistance)
5. Integration: Integrase incorporates HIV DNA (proviral DNA) into host genome - target of integrase inhibitors (dolutegravir, raltegravir)
6. Transcription: Tat protein activates transcription of viral genes using host machinery
7. Translation & Assembly: Viral proteins made; Gag/Pol polyprotein assembled at cell membrane
8. Budding & Maturation: Protease cleaves polyprotein into functional units - target of protease inhibitors (ritonavir, lopinavir)

Key exam point: Rapid error-prone replication (~10^9 new virions/day) generates viral diversity; variants with resistance mutations to individual antiretroviral agents already preexist before treatment begins.

• Goldman-Cecil Medicine 22e, p. 3687

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3. Immunopathogenesis

1. Direct cytopathic effect - HIV replication kills infected CD4+ T cells
2. Syncytia formation - HIV Env gp120 induces fusion of uninfected CD4+ T cells → apoptosis of uninfected cells (bystander killing)
3. Immune exhaustion - Persistent viral antigen leads to T-cell anergy
4. Impaired thymopoiesis - Reduced naive T-cell production over time

Note: HIV is highly cytopathic to CD4+ T lymphocytes but not to monocytes/macrophages - macrophages act as a reservoir.

• Sherris & Ryan's Medical Microbiology, 8e, p. 288; Goldman-Cecil Medicine 22e, p. 3692

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4. Natural History & CD4 Count Thresholds

Primary HIV Infection  →  Clinical Latency  →  AIDS
(acute retroviral       (virus replicating      (CD4 < 200 cells/μL
syndrome, 2-4 wk)      high-level; CD4 ↓)      or AIDS-defining illness)

CD4 Count - Opportunistic Infection Thresholds (HIGH-YIELD TABLE)

• Goldman-Cecil Medicine 22e, p. 3692

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5. Clinical Stages

Stage 1 - Acute HIV (Primary Infection)

• Occurs 2-4 weeks after exposure
• Mononucleosis-like syndrome: fever, lymphadenopathy, pharyngitis, rash, myalgia, headache
• High viral load; CD4 may transiently drop
• Window period: p24 Ag detectable at ~2 weeks; antibodies appear later

Stage 2 - Clinical Latency (Chronic HIV)

• Asymptomatic or mild symptoms (e.g., persistent generalized lymphadenopathy in 50-70%)
• Virus actively replicating; CD4 declining ~50-100 cells/μL per year
• Can last 10+ years untreated

Stage 3 - AIDS

• CD4 < 200 cells/μL OR presence of an AIDS-defining illness
• Constitutional symptoms: weight loss, night sweats, chronic diarrhea
• Opportunistic infections and AIDS-defining neoplasms

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6. AIDS-Defining Opportunistic Infections

Fungi

Parasites

Viruses

Bacteria

• Jawetz Melnick & Adelbergs Medical Microbiology 28e, p. 3862-3882; Goldman-Cecil Medicine 22e, p. 3692-3693

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7. Nervous System Complications

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8. Antiretroviral Therapy (ART)

Drug Classes

When to Start ART

• Recommended in all HIV-infected individuals, regardless of CD4 count
• Start as soon as possible after diagnosis
• For opportunistic infections: generally start within 2 weeks; exceptions:
  • TB co-infection (CD4 <50): Start ART within 2 weeks of TB treatment
  • TB co-infection (CD4 >50): Can delay up to 8 weeks
  • Cryptococcal meningitis: Delay ART 4-6 weeks after antifungal therapy (IRIS risk)

Treatment Goals

• Viral load suppressed to undetectable (<20 copies/mL)
• CD4 count recovery (normalization expected with adherence)
• Prevention of opportunistic infections

Standard First-Line Regimen

• Goldman-Cecil Medicine 22e, p. 3696; Goldman-Cecil Medicine 22e, p. 3692

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9. PEP and PrEP

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10. Diagnosis

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11. IRIS - Immune Reconstitution Inflammatory Syndrome

• Occurs when ART rapidly suppresses viral load in someone with advanced disease (CD4 <100)
• Exaggerated inflammatory response to previously subclinical opportunistic pathogens
• Classic triggers: TB, MAC, CMV, Cryptococcus
• Presentation: paradoxical worsening of OI symptoms after starting ART
• Management: Continue ART; NSAIDs or corticosteroids for severe cases; delay ART start in cryptococcal meningitis

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12. Transmission

U = U (Undetectable = Untransmittable): A person with a fully suppressed viral load on ART cannot transmit HIV sexually.

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13. Quick-Reference: Exam Favorites

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• Goldman-Cecil Medicine International Edition, 22e
• Jawetz, Melnick & Adelberg's Medical Microbiology, 28e
• Sherris & Ryan's Medical Microbiology, 8e
• Harrison's Principles of Internal Medicine, 22e (2025)