PA8.6 | HIV & AIDS — Summary & Reflection

REFLECT

Consider the molecular basis of ART targeting. Every class of antiretroviral drug targets a step in the HIV replication cycle you have just studied:

• NRTIs/NNRTIs → reverse transcriptase (block RNA→DNA step)
• Integrase inhibitors → integrase (block provirus formation)
• Protease inhibitors → protease (block polyprotein cleavage → non-infectious virions)
• Entry/fusion inhibitors → gp120–CD4 binding or gp41-mediated fusion
• CCR5 antagonists (maraviroc) → CCR5 co-receptor (effective only against R5 strains)

Reflect: Why does combination therapy with three or more drugs from different classes work where monotherapy fails? Think about the error rate of reverse transcriptase, the enormous daily viral output (~10⁹ virions), and the probability of a single virion carrying resistance mutations to three unrelated drug classes simultaneously. This principle — high mutation rate defeated by hitting multiple targets at once — applies to cancer chemotherapy and anti-TB therapy for the same mathematical reason.

KEY TAKEAWAYS

HIV & AIDS — Core Framework:

Structure: Retrovirus; ssRNA + RT + integrase + protease; gp120 (CD4/co-receptor binding) + gp41 (fusion)

Transmission: Sexual (most common) > parenteral > vertical; NOT by casual contact

Entry: gp120 → CD4 → CCR5 (macrophage-tropic) or CXCR4 (T-cell-tropic) → membrane fusion → provirus integration

CD4 depletion mechanisms: Direct cytopathic effect, CTL killing, pyroptosis (major), syncytia, thymic damage, chronic immune activation

Natural history:
1. Acute phase: peak viraemia, seroconversion illness, window period
2. Chronic latency: 8–10 years, gradual CD4 decline (~50/year)
3. AIDS: CD4 < 200 or AIDS-defining illness

OI thresholds: < 500 TB; < 200 PCP; < 100 Toxoplasma/Cryptococcus; < 50 CMV/MAC

AIDS malignancies: KS (HHV-8), NHL/Burkitt (EBV), cervical carcinoma (HPV)

Diagnosis: 4th-gen ELISA (screen) → Western blot (confirm); p24 Ag earliest; RNA PCR for window period; CD4 for staging; viral load for monitoring

ART: ≥ 3 drugs / ≥ 2 classes; goal = undetectable viral load; U=U