# HIV Antiretroviral Drugs by Life Cycle

> How does HIV replicate and which drug class targets each step?

Seven steps from CD4 binding to protease maturation, each matched to the drug class that blocks it, with the toxicities boards ask about.

HIV binds CD4 using a CCR5 or CXCR4 coreceptor, fuses through gp41, reverse-transcribes its RNA into DNA, integrates that DNA, transcribes new virions, then matures when viral protease cleaves its polyproteins. Entry inhibitors, NRTIs, NNRTIs, integrase inhibitors and protease inhibitors each block one step, and first-line therapy combines two NRTIs with an integrase inhibitor.

## How does HIV replicate and which drug class targets each step?

Every antiretroviral question is a life-cycle question: the exam names a drug and asks which step it blocks, or names a toxicity and asks for the drug. Learning the cycle in order collapses thirty drugs into seven mechanisms.

HIV is an enveloped retrovirus carrying two copies of positive-sense single-stranded RNA plus its own reverse transcriptase, integrase and protease. Its **env** product is cleaved into surface **gp120** and transmembrane **gp41**; **pol** encodes the three enzymes. Reverse transcriptase has no proofreading exonuclease, so HIV mutates constantly -- which is why monotherapy always fails. Entry inhibitors act outside the cell; enzyme inhibitors act inside. Nothing eradicates integrated provirus, so therapy is lifelong suppression, not cure.

## The HIV life cycle runs in seven steps

1. **Attachment.** gp120 binds **CD4** on helper T cells, macrophages and dendritic cells, then shifts conformation to expose the coreceptor site.
2. **Coreceptor binding.** gp120 engages **CCR5** on macrophages -- the tropism of most transmitted strains, absent in CCR5-Δ32 homozygotes, who resist infection -- or **CXCR4** on T cells, dominant later in disease.
3. **Fusion.** gp41 inserts its fusion peptide into the host membrane and pulls the bilayers together, delivering the capsid into the cytoplasm.
4. **Reverse transcription.** Reverse transcriptase copies viral RNA into double-stranded DNA, degrading the template with RNase H activity.
5. **Integration.** **Integrase** inserts that DNA into the host chromosome as a provirus, which persists for the life of the cell.
6. **Transcription and translation.** Host RNA polymerase II transcribes the provirus; ribosomes make Gag and Gag-Pol polyproteins and envelope glycoprotein.
7. **Budding and maturation.** The particle buds through the membrane, and **HIV protease** cleaves the polyproteins into functional proteins. Without that cleavage the virion is noninfectious.

## Each antiretroviral class maps to one step

| Class | Step Targeted | Example Drugs | Key Side Effect | Board Pearl |
| --- | --- | --- | --- | --- |
| NRTIs | Reverse transcription (chain terminator) | Tenofovir, emtricitabine, lamivudine, abacavir, zidovudine | Mitochondrial toxicity: lactic acidosis, hepatic steatosis | Need intracellular phosphorylation; tenofovir is a nucleotide |
| NNRTIs | Reverse transcription (allosteric site) | Efavirenz, nevirapine, rilpivirine, doravirine | Rash, hepatotoxicity, CYP450 interactions | Noncompetitive, need no phosphorylation, never cover HIV-2 |
| Protease inhibitors | Maturation after budding | Atazanavir, darunavir, lopinavir, ritonavir, indinavir | Lipodystrophy, hyperglycemia, hyperlipidemia | All end in **-navir**; ritonavir is a CYP3A4-inhibiting booster |
| Integrase strand transfer inhibitors | Integration of proviral DNA | Dolutegravir, bictegravir, raltegravir | Weight gain, insomnia, headache | All end in **-tegravir**; antacid and iron cations chelate them |
| CCR5 antagonists | Coreceptor binding | Maraviroc | Hepatotoxicity | Needs a tropism assay -- useless against CXCR4-tropic virus |
| Fusion inhibitors | gp41-mediated fusion | Enfuvirtide | Injection-site reactions | Subcutaneous only; a salvage drug |
| Attachment and capsid agents | Attachment, post-attachment, capsid | Fostemsavir, ibalizumab, lenacapavir | Infusion or injection-site reactions | For multidrug-resistant HIV; lenacapavir is long-acting |

> **If you only remember one thing:** the order is entry (maraviroc, enfuvirtide) -> reverse transcription (NRTIs, NNRTIs) -> integration (**-tegravir**) -> maturation (**-navir**). First-line therapy is two NRTIs plus an integrase inhibitor.

## Side effect associations decide most drug questions

- **Efavirenz:** vivid dreams, nightmares and dizziness early on, plus a false-positive cannabinoid screen.
- **Tenofovir disoproxil fumarate:** nephrotoxicity with proximal tubular injury, and decreased bone mineral density. Tenofovir alafenamide spares both.
- **Abacavir:** systemic hypersensitivity with fever, rash and GI symptoms. Test **HLA-B*5701** before prescribing; never rechallenge.
- **Zidovudine:** bone marrow suppression -- macrocytic anemia, neutropenia -- plus myopathy.
- **Protease inhibitors:** lipodystrophy, insulin resistance, hyperlipidemia and dense CYP3A4 interactions. **Indinavir** causes crystalluria and nephrolithiasis; **atazanavir** causes benign indirect hyperbilirubinemia.
- **Nevirapine:** hepatotoxicity and severe rash including Stevens-Johnson syndrome.
- **Integrase inhibitors:** the best-tolerated class; weight gain is the main concern.

## Start ART at diagnosis, in a combination of at least three drugs

Treat every patient with HIV regardless of CD4 count or viral load, within days of diagnosis. A standard regimen is **two NRTIs plus an integrase strand transfer inhibitor**: tenofovir with emtricitabine or lamivudine, plus bictegravir or dolutegravir. Combination therapy is mandatory because error-prone reverse transcriptase generates resistant variants daily: three active drugs make simultaneous mutations improbable, while one drug selects a resistant clone within weeks.

One exception: with **cryptococcal** or **tuberculous meningitis**, ART is delayed to reduce fatal immune reconstitution inflammatory syndrome. Opportunistic-infection prophylaxis runs alongside ART by CD4 threshold, covered in [HIV and the CD4 count](/blog/hiv-aids-cd4-count-usmle), using drugs from the [antibiotic coverage](/blog/antibiotic-mechanisms-coverage-usmle) tables.

## Perinatal prevention and post-exposure prophylaxis follow fixed rules

Every pregnant patient with HIV takes ART throughout pregnancy, aiming at viral suppression. If the viral load near delivery exceeds 1,000 copies/mL or is unknown, give **intrapartum IV zidovudine** and perform a **scheduled cesarean at 38 weeks**. The newborn gets antiretroviral prophylaxis; US practice favors formula feeding, though durable suppression now permits breastfeeding after counseling.

After occupational or sexual exposure, start **post-exposure prophylaxis within 72 hours** -- sooner is better -- and continue three drugs, typically tenofovir/emtricitabine plus an integrase inhibitor, for 28 days. Pre-exposure prophylaxis requires a documented negative HIV test first, since two drugs during acute infection select resistance.

## Resistance testing guides every regimen change

Order **genotypic resistance testing** at entry into care and at virologic failure. **M184V**, selected by lamivudine and emtricitabine, causes high-level resistance to both but reduces viral fitness and resensitizes the virus to zidovudine and tenofovir. **K65R**, selected by tenofovir, cuts tenofovir and abacavir susceptibility while increasing zidovudine susceptibility. **K103N** confers efavirenz and nevirapine resistance at no fitness cost.

## How this is tested on the exam

- **Stem:** fever, rash and malaise ten days after starting abacavir. **Answer:** abacavir hypersensitivity -- stop permanently; HLA-B*5701 should have been checked first.
- **Stem:** rising creatinine with glucosuria and normal serum glucose on tenofovir disoproxil. **Answer:** proximal tubulopathy; switch to tenofovir alafenamide.
- **Stem:** worsening lymphadenopathy two weeks after starting ART, with falling viral load and rising CD4. **Answer:** IRIS -- continue ART, treat the unmasked infection.

## Common wrong-answer traps

- **Waiting for the CD4 count to drop.** ART begins at diagnosis, at any CD4 count.
- **Adding one drug to a failing regimen.** That is functional monotherapy; change at least two active agents by genotype.
- **Confusing maraviroc with enfuvirtide.** Maraviroc blocks the host CCR5 coreceptor and needs a tropism assay; enfuvirtide blocks gp41 fusion.
- **Placing protease inhibitors before budding.** Protease acts at maturation, so blocking it releases immature, noninfectious virions.

The organism side of these vignettes sits in the [Infectious Disease](/topics/infectious-disease) hub.

## Sources

- [IDSA HIV Practice Guidelines](https://www.idsociety.org/practice-guideline/practice-guidelines/)
- [CDC -- HIV](https://www.cdc.gov/hiv/)
- [USMLE Step 1](https://www.usmle.org/step-exams/step-1)

Antiretroviral pharmacology is pure recall and decays fast. [Practice HIV pharmacology questions on StepGenie](https://dashboard.stepgenie.app/sign-up) until every drug snaps back to its step and toxicity.

## Frequently asked questions

### Which drug class blocks each step of the HIV life cycle?

Maraviroc blocks CCR5 coreceptor binding and enfuvirtide blocks gp41-mediated fusion, so both are entry inhibitors. NRTIs and NNRTIs both stop reverse transcription, NRTIs as chain terminators and NNRTIs at an allosteric site. Integrase strand transfer inhibitors, the drugs ending in -tegravir, block integration of viral DNA into the host chromosome. Protease inhibitors, ending in -navir, block maturation after budding.

### What is the standard first-line HIV regimen and why are three drugs needed?

First-line antiretroviral therapy is two NRTIs plus an integrase strand transfer inhibitor, such as tenofovir with emtricitabine plus bictegravir or dolutegravir, started at diagnosis regardless of CD4 count. Three active drugs are required because HIV reverse transcriptase lacks proofreading and generates resistant variants continuously. Suppressing replication with one or two agents simply selects the resistant clone, whereas simultaneous resistance to three drugs is far less likely.

### Which antiretroviral side effects show up most on USMLE questions?

Efavirenz causes vivid dreams and other neuropsychiatric effects. Tenofovir disoproxil causes proximal tubular nephrotoxicity and bone mineral density loss. Abacavir causes a hypersensitivity reaction, so test HLA-B*5701 first. Zidovudine causes bone marrow suppression. Protease inhibitors cause lipodystrophy, hyperglycemia and CYP3A4 interactions, with indinavir causing nephrolithiasis. Nevirapine causes hepatotoxicity and Stevens-Johnson syndrome, and integrase inhibitors cause weight gain.

### What do the M184V and K65R mutations mean on an HIV genotype?

M184V is selected by lamivudine and emtricitabine and confers high-level resistance to both, but it reduces viral replication fitness and increases susceptibility to zidovudine and tenofovir, so it is sometimes tolerated deliberately. K65R is selected by tenofovir and reduces susceptibility to tenofovir and abacavir while increasing zidovudine susceptibility. Order genotypic resistance testing at entry into care and again at virologic failure.

### How soon must post-exposure prophylaxis be started after an HIV exposure?

Start post-exposure prophylaxis as soon as possible and within 72 hours of an occupational or sexual exposure, since efficacy falls sharply with delay. The regimen is three drugs, typically tenofovir with emtricitabine plus an integrase inhibitor, continued for 28 days with follow-up HIV testing. Pre-exposure prophylaxis is different: it requires a documented negative HIV test first, because starting two drugs during acute infection selects resistance.

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Canonical page: [HIV Antiretroviral Drugs by Life Cycle](https://www.stepgenie.app/blog/hiv-antiretroviral-drugs-usmle)
Topic hub: [Infectious Disease](https://www.stepgenie.app/topics/infectious-disease)