Everything You Need to Know About HIV lifecycle & drugs for Step 1

HIV is one of those “small genome, huge consequences” viruses that shows up everywhere on Step 1—mechanisms, immunology, drugs, adverse effects, opportunistic infections, and test-taking traps. If you can mentally “walk” HIV through its lifecycle and pin each drug class to a specific step, a big chunk of micro + pharm questions become plug-and-play.

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The 10,000-foot definition (what HIV is)

Human Immunodeficiency Virus (HIV) is an enveloped, +ssRNA retrovirus (genus Lentivirus) that primarily infects CD4+ T cells, macrophages, and dendritic cells, leading to progressive immunodeficiency and, if untreated, AIDS.

High-yield structure/genetics

• Enveloped → susceptible to detergents/drying; spreads via blood/sexual/perinatal routes (not casual contact).
• Two copies of +ssRNA (diploid genome) inside a conical capsid (p24).
• Key enzymes packaged in the virion:
  • Reverse transcriptase
  • Integrase
  • Protease
• Key surface proteins:
  • gp120: binds CD4 and a co-receptor
  • gp41: mediates fusion

First Aid cross-reference: Microbiology → Virology → Retroviruses (HIV); Pharmacology → Antiretrovirals.

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HIV lifecycle (Step 1 “map it to a drug” edition)

Think of the lifecycle as a sequence of “verbs.” Each verb is a drug target.

1) Attachment (docking)

• gp120 binds CD4 on host cells.
• Then gp120 binds a co-receptor:
  • CCR5 (often early infection; macrophage-tropic)
  • CXCR4 (often later infection; T-cell tropic)

Drug target

• CCR5 antagonist: Maraviroc
  • Blocks CCR5, preventing gp120 co-receptor binding.
  • Requires tropism testing (works only for CCR5-tropic virus).

HY association: Some individuals with CCR5-Δ32 mutation are resistant to infection by CCR5-tropic HIV (classic board fact).

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2) Fusion/entry (membranes merge)

• gp41 drives fusion of viral envelope with host cell membrane.

Drug target

• Fusion inhibitor: Enfuvirtide
  • Binds gp41 → prevents fusion/entry.

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3) Reverse transcription (RNA → DNA)

• Reverse transcriptase makes a DNA copy from viral RNA, then forms dsDNA.
• Reverse transcriptase is error-prone → high mutation rate → resistance is common if adherence is poor.

Drug targets

• NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors)
• NNRTIs (non-nucleoside reverse transcriptase inhibitors)

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4) Integration (viral DNA into host genome)

• Integrase inserts viral dsDNA into host DNA → provirus (latency reservoir).

Drug target

• INSTIs (integrase strand transfer inhibitors): e.g., Raltegravir, Dolutegravir, Bictegravir

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5) Transcription/translation (host machinery makes viral proteins)

• Host cell transcribes proviral DNA → viral RNA genomes and mRNAs.
• Viral proteins synthesized as polyproteins.

(No major Step 1 drug class “lives” here—just understand host dependence and latency.)

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6) Assembly, budding, maturation (protease makes it infectious)

• Virions bud from host membrane (enveloped).
• Protease cleaves polyproteins into functional proteins → maturation into infectious virion.

Drug target

• Protease inhibitors (PIs): e.g., -navir drugs (Darunavir, Atazanavir, etc.)

Memory hook: If protease is inhibited, the virus “buds” but is immature and noninfectious.

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Antiretroviral drug classes: step, examples, and board-relevant toxicity

Quick table (high-yield Step 1 layout)

First Aid cross-reference: Pharmacology → Antiretroviral drugs (NRTIs, NNRTIs, PIs, INSTIs, entry inhibitors).

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NRTIs (Reverse transcriptase “fake building blocks”)

Mechanism

• NRTIs are phosphorylated and competitively inhibit reverse transcriptase and terminate DNA chain elongation (lack 3′-OH, conceptually).
• Also inhibit mitochondrial DNA polymerase → mitochondrial toxicity.

High-yield toxicities you should know cold

• Zidovudine (AZT): bone marrow suppression → anemia, neutropenia
  • Also used historically in pregnancy; still relevant conceptually for perinatal transmission prevention.
• Abacavir: hypersensitivity reaction (potentially fatal)
  • Strong association with HLA-B*57:01 → screen before starting.
• Tenofovir (TDF): nephrotoxicity (proximal tubule injury/Fanconi-like), ↓ bone mineral density
  • Tenofovir + emtricitabine is common in PrEP.
• Didanosine, Stavudine (older, less used): pancreatitis, peripheral neuropathy
• Class effect: lactic acidosis, hepatic steatosis (mitochondrial toxicity)

Step 1 pitfall: NRTIs vs NNRTIs—both hit reverse transcriptase, but NRTIs require phosphorylation and can cause mitochondrial toxicity.

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NNRTIs (Reverse transcriptase “allosteric inhibitors”)

Mechanism

• Bind noncompetitively to reverse transcriptase (allosteric site) → inhibit RNA→DNA transcription.
• Do not require phosphorylation.

High-yield adverse effects

• Efavirenz: CNS effects (vivid dreams, dizziness), neuropsychiatric symptoms; also classically teratogenic on exams.
• Nevirapine: hepatotoxicity, rash (SJS/TEN can be tested).
• Class: rash, hepatotoxicity, significant drug interactions (CYP effects vary by agent).

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Protease inhibitors (Stop maturation)

Mechanism

• Inhibit HIV protease → prevent cleavage of gag-pol polyprotein → noninfectious virions.

High-yield adverse effects

• Metabolic syndrome: insulin resistance, hyperglycemia
• Hyperlipidemia
• Lipodystrophy (“buffalo hump,” central adiposity, peripheral wasting)
• CYP450 interactions: many PIs are boosted with ritonavir (CYP inhibition) to increase levels of the primary PI.

Classic “exam phrase”: “Patient on -navir develops dyslipidemia and fat redistribution.”

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Integrase inhibitors (Block integration)

Mechanism

• Inhibit integrase strand transfer → viral DNA cannot integrate into host genome.

High-yield notes

• Common backbone agents in modern therapy due to potency and tolerability.
• Boards may test the step (integration) more than specific toxicities.

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Entry inhibitors recap (attachment/fusion)

• Maraviroc: CCR5 co-receptor antagonist (attachment)
• Enfuvirtide: gp41 fusion inhibitor (fusion)

HY clinical tie-in: Co-receptor usage can shift over time (CCR5 early, CXCR4 later)—a concept that helps with pathophysiology questions.

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Pathophysiology (why CD4 count matters)

Key idea: progressive CD4 depletion + chronic immune activation

• Early: massive viral replication, especially in gut-associated lymphoid tissue → sharp CD4 drop, then partial recovery.
• Set point: viral load stabilizes at a patient-specific level; predicts progression speed.
• Late: gradual CD4 decline → opportunistic infections/malignancies.

AIDS definition (exam-standard)

• CD4 < 200 cells/mm³ or an AIDS-defining illness (even if CD4 higher).

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Clinical presentation by stage (how it shows up in stems)

1) Acute retroviral syndrome (2–4 weeks after exposure)

• Flu/mono-like: fever, sore throat, lymphadenopathy, rash
• Often mucocutaneous ulcers
• Labs: high viral load, low CD4, negative (or indeterminate) antibody early

Test-taking clue: “Mononucleosis-like illness but heterophile antibody test negative” → think acute HIV.

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2) Chronic HIV (clinical latency)

• Often asymptomatic or persistent generalized lymphadenopathy.
• Ongoing replication in lymphoid tissue.

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3) AIDS / advanced HIV

Symptoms are driven by opportunistic infections (OIs) and malignancies.

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Opportunistic infections & malignancies: tie to CD4 thresholds (core Step 1)

Extremely high-yield thresholds table

First Aid cross-reference: Microbiology → Opportunistic infections in AIDS; Immunology → CD4 functions and immunodeficiency patterns.

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Diagnosis (what test to order and when)

Screening algorithm (modern, testable concept)

• 4th-generation HIV test: detects p24 antigen + anti-HIV antibodies
  • Becomes positive earlier than antibody-only tests.

Acute infection / very early window period

• If high suspicion but screening negative/indeterminate:
  • Order HIV RNA (NAT/PCR)

Monitoring disease

• Viral load (HIV RNA): best for treatment response
• CD4 count: best for OI risk assessment and prophylaxis decisions

HY trap: In acute infection, p24 antigen and RNA rise before antibodies; early antibody tests can be negative.

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Treatment: the Step 1 framework (what “ART” means)

Standard principle: Treat with combination antiretroviral therapy to suppress replication and prevent resistance.

A common exam-friendly way to remember the concept:

• 2 NRTIs + 1 additional agent (often an INSTI in modern regimens)

You don’t need to memorize specific real-world combos for Step 1 as much as you need:

• Which lifecycle step each class blocks
• High-yield toxicities
• Why combination therapy prevents resistance

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Prevention: PrEP and PEP (frequently tested)

PrEP (pre-exposure prophylaxis)

• For high-risk HIV-negative individuals
• Classic regimen tested: Tenofovir + Emtricitabine (both NRTIs)

PEP (post-exposure prophylaxis)

• After needlestick/sexual exposure when indicated; start ASAP (conceptually within hours)
• Uses a 3-drug ART regimen (often includes an INSTI + 2 NRTIs)

Test emphasis: Recognize scenarios (needle stick, unprotected sex with known HIV+) and that rapid initiation matters.

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High-yield “exam sentence” associations

• gp120 binds CD4; gp41 mediates fusion
• Reverse transcriptase is error-prone → resistance risk with poor adherence
• Integrase inserts viral DNA into host genome (latent reservoir)
• Protease is required for maturation → PIs cause noninfectious viral particles
• AIDS = CD4 < 200 or AIDS-defining illness
• PJP at <200, Toxo/Crypto at <100, CMV/MAC at <50
• Abacavir hypersensitivity ↔ HLA-B*57:01
• Tenofovir nephrotoxicity + ↓ bone density
• Zidovudine anemia (bone marrow suppression)
• Efavirenz CNS/teratogenic (classic boards framing)
• PIs → metabolic syndrome/lipodystrophy + CYP interactions

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Rapid self-check (mini practice prompts)

1. Patient with HIV starts a drug and develops anemia/neutropenia → which drug?
   • Zidovudine
2. Drug blocks fusion by binding gp41 →
   • Enfuvirtide
3. CD4 = 45 with visual floaters and retinal hemorrhages →
   • CMV retinitis
4. HIV test negative but high suspicion 10 days after exposure →
   • HIV RNA (NAT/PCR)