Human immunodeficiency virus Study Guide

📖 Core Concepts HIV = retrovirus (Lentivirus) that causes AIDS – progressive loss of CD4⁺ T‑cell immunity. Target cells: CD4⁺ T helper cells, macrophages, dendritic cells. Entry: gp120 binds CD4 → conformational change → CCR5 or CXCR4 co‑receptor → gp41‑mediated membrane fusion. Replication: RT → DNA → integrase inserts provirus → transcription (Tat, Rev) → translation (Gag‑Pol, Env) → assembly → protease‑mediated maturation. Co‑receptor tropism: R5 (CCR5‑tropic) – dominates early infection, infects macrophages & T cells. X4 (CXCR4‑tropic) – emerges later, linked to rapid CD4 decline. Genetic variability: Extremely high mutation rate ($\sim3\times10^{-5}$ per nt per cycle) + copy‑choice recombination (2–20 events/genome). Diagnosis: CD4 count, plasma viral load, ELISA screening → confirm with Western blot, PCR/NAT. Treatment: Combination ART (≥3 drugs) → suppresses viral load < 50 copies/mL → U = U (undetectable = untransmittable). --- 📌 Must Remember Survival without treatment: 9–11 years after infection. Transmission: Sexual fluids, blood, mother‑to‑child; undetectable = non‑transmissible. HIV‑1 vs HIV‑2: HIV‑1 = more virulent, global; HIV‑2 = West Africa, slower progression. Co‑receptor switch: R5 → X4 → faster AIDS progression. CCR5‑Δ32 homozygotes: Resistant to R5 viruses. Mutation rate: $3\times10^{-5}$ mutations/nt/replication; $10^{10}$ virions/day. Recombination contribution: 15–20 % of genetic variation. Basic reproduction number: $R{0}=2$–5 for HIV. Key viral genes & functions: gag, pol, env – structural/enzymatic. tat – LTR transcription activation. rev – nuclear export of unspliced RNAs. nef – down‑regulates CD4 & MHC I. vif – counters APOBEC3G. vpr – G2/M arrest. vpu – enhances virion release. --- 🔄 Key Processes Entry gp120 ↔ CD4 → expose co‑receptor site → bind CCR5/CXCR4 → gp41 hairpin pulls membranes together → fusion. Reverse Transcription RT copies two RNA genomes → single‑stranded DNA → RNase H degrades RNA → double‑stranded DNA. Integration Integrase inserts DNA into host genome → provirus (latent or active). Transcription & RNA Processing NF‑κB activation → LTR transcription → full‑length RNA (genome + mRNA) + spliced RNAs. Rev binds Rev response element → exports unspliced/partially spliced RNAs. Translation & Assembly Gag polyprotein drives capsid formation at plasma membrane. Env (gp160) → ER/Golgi → gp120 + gp41 → transported to membrane. Budding & Maturation Immature particle buds → viral protease cleaves Gag/Gag‑Pol → mature, infectious virion. Cell‑to‑Cell Spread Virological synapse → direct transfer of virions → >10× efficiency vs cell‑free spread. --- 🔍 Key Comparisons R5 (CCR5‑tropic) vs X4 (CXCR4‑tropic) Receptor: CCR5 vs CXCR4 Cell types: Macrophages + T cells vs primarily T cells Stage: Early transmission vs later disease progression Clinical impact: Slower CD4 loss vs rapid decline HIV‑1 vs HIV‑2 Virulence: HIV‑1 higher Transmission: HIV‑1 more efficient Geography: HIV‑1 worldwide, HIV‑2 West Africa Disease course: HIV‑2 slower Cell‑free vs Cell‑to‑cell spread Efficiency: Cell‑to‑cell ≫ cell‑free Drug susceptibility: Cell‑to‑cell less affected by ART concentrations Mode: Virions in extracellular fluid vs virological synapse --- ⚠️ Common Misunderstandings “Undetectable means cured.” → Undetectable viral load stops transmission but latent reservoirs persist. All HIV uses CCR5. → X4‑tropic strains appear in 50 % of patients during later stages. ELISA alone confirms infection. → Positive ELISA must be confirmed by Western blot, PCR, or antigen/antibody differentiation. Only CD4 count matters for treatment decisions. → Viral load and resistance testing are equally critical. HIV‑2 is harmless. → It still causes AIDS, just slower; ART is still indicated. --- 🧠 Mental Models / Intuition “Lock & key → door opening.” gp120 = key that fits CD4 (lock); co‑receptor binding turns the key, allowing gp41 (door hinge) to open the membrane door. “Factory line.” Reverse transcription = raw material conversion; integration = blueprint insertion; transcription/translation = production; protease = quality‑control finishing. “Highway vs side‑street.” Cell‑free spread = highway (long distance, slower traffic); cell‑to‑cell spread = side‑street shortcut (fast, high‑density traffic). --- 🚩 Exceptions & Edge Cases CCR5‑Δ32 homozygotes: resistant to R5 strains but can still be infected by X4 viruses. Elite controllers: Rare individuals maintain < 50 copies/mL without ART → strong cytotoxic CD8 response. Acute infection window period: Antibody tests negative; p24 antigen or NAT needed for early detection. Dual‑tropic (R5X4) viruses: Can use both co‑receptors, complicating tropism‑based therapies. --- 📍 When to Use Which Screening test → ELISA (high sensitivity). Confirmatory test → Western blot or differentiation immunoassay (antibody profile) or NAT if antibody results indeterminate. ART regimen selection → Include at least two NRTIs + one integrase inhibitor or NNRTI; consider resistance profile. Co‑receptor antagonist (maraviroc) → Only when tropism testing shows pure R5 virus. PEP vs PrEP → PEP = within 72 h post‑exposure, 28‑day course; PrEP = daily oral tenofovir/emtricitabine for ongoing risk. --- 👀 Patterns to Recognize R5‑tropic → early infection, high viral load, slower CD4 decline. Switch to X4 tropism → sudden CD4 drop, rapid progression. Elevated viral load + falling CD4 = treatment failure → check adherence/resistance. Presence of N‑linked high‑mannose glycans on gp120 → immune evasion (“glycan shield”). Multiple mutations in protease + reverse transcriptase → multidrug resistance (watch for pattern of cross‑resistance). --- 🗂️ Exam Traps “Undetectable = no virus.” – Wrong: latent reservoirs remain. Choosing CCR5 antagonist for X4‑tropic infection. – Wrong: ineffective, may select for X4. Assuming HIV‑2 is not treated. – Wrong: ART indicated, though some regimens differ. Confusing reverse transcriptase error rate with mutation rate per genome. – Remember $3\times10^{-5}$ per nucleotide per cycle; leads to 1 mutation per genome per replication. Mixing up gag vs env functions. – gag = structural proteins; env = gp120/gp41 entry proteins. ---