human immunodeficiency virus

**Structure and genome** - Enveloped, diploid (two copies), positive-sense ssRNA retrovirus. It carries reverse transcriptase, integrase, and protease within the virion. - gag encodes structural proteins: p24 (capsid) and p17 (matrix). p24 is the target of the antigen component of 4th-generation tests. - pol encodes reverse transcriptase, integrase, and protease. - env encodes gp120 and gp41. gp120 mediates attachment to CD4 and a coreceptor. gp41 mediates fusion and entry. - Other regulatory genes include tat, rev, nef, vif, vpr, and vpu.

**Pathogenesis** 1. gp120 binds CD4 on T-helper cells, macrophages, and dendritic cells. 2. The virus then binds a coreceptor: CCR5 for early or macrophage-tropic strains, or CXCR4 for late or T-cell-tropic strains. Individuals homozygous for the CCR5-Δ32 mutation are resistant to infection. 3. gp41 mediates fusion and entry. 4. Reverse transcriptase makes dsDNA, which integrase inserts into the host genome as a provirus. Latent reservoirs persist in resting memory CD4+ T cells. 5. Viral proteins are assembled, and protease cleaves the polyprotein precursors into mature proteins before the virion buds. - CD4+ T cells are depleted by direct cytopathic effect, CD8+ T-cell-mediated killing, and immune activation or exhaustion. This impairs cell-mediated immunity. - Rapid mutation (error-prone reverse transcriptase) allows immune escape. Phenotypic mixing and genetic reassortment can occur if a cell is coinfected with two strains.

**Transmission** - Sexual contact (the most common route worldwide), including receptive anal intercourse, which carries the highest per-act risk. - Parenteral: IV drug use with shared needles and blood transfusion (now very rare). - Vertical: transplacental, during delivery, or via breastfeeding. - Needlestick exposure carries roughly a 0.3% risk.

**Clinical course** - *Acute (primary) infection*, 2–4 weeks after exposure: mononucleosis-like illness with fever, pharyngitis, lymphadenopathy, and rash. Viral load is very high and antibody tests may be negative (the window period). - *Clinical latency*: asymptomatic, with the CD4 count slowly declining over years. Viral set point predicts the rate of progression. - *AIDS*: CD4 <200 cells/mm³ or an AIDS-defining condition. Long-term nonprogressors and elite controllers are rare exceptions.

**Opportunistic infections and malignancies by CD4 count** - <500: candidal thrush (oropharyngeal), TB reactivation, HPV disease, and other early infections. - <200: *Pneumocystis jirovecii* pneumonia (PCP) and HIV-associated dementia or wasting. Start PCP prophylaxis with TMP-SMX. - <100: *Toxoplasma gondii* encephalitis (ring-enhancing lesions), cryptococcal meningitis, and esophageal candidiasis. Start toxoplasmosis prophylaxis with TMP-SMX if IgG is positive. Primary CNS lymphoma (EBV-associated) is another consideration. - <50: disseminated *Mycobacterium avium* complex (MAC) and CMV retinitis or colitis. Azithromycin prophylaxis for MAC is no longer routinely recommended if ART is started right away. - Other findings: Kaposi sarcoma (HHV-8), cervical and anal carcinoma (HPV), non-Hodgkin lymphoma, oral hairy leukoplakia (EBV), and PML (JC virus).

**Diagnosis** - Screening: 4th-generation HIV-1/2 antigen/antibody combination immunoassay (detects p24 antigen plus antibodies). - Positive screens are confirmed with an HIV-1/HIV-2 antibody differentiation immunoassay. - Indeterminate or discordant results are followed by an HIV-1 RNA (NAT) viral load test. - In infants born to HIV-positive mothers, use HIV RNA/DNA PCR. Maternal IgG can cross the placenta and cause false-positive antibody tests for up to 18 months. - Monitor with CD4 count (disease status) and viral load (treatment response).

**Treatment (ART)** - ART is recommended for all patients regardless of CD4 count. The standard regimen is two NRTIs plus a third agent, usually an INSTI. - NRTIs (e.g., tenofovir, emtricitabine, abacavir, lamivudine, zidovudine) inhibit reverse transcriptase. - Zidovudine causes anemia and bone marrow suppression. - Tenofovir can cause nephrotoxicity. - Abacavir causes a hypersensitivity reaction in HLA-B*5701 carriers, so screen before use. - NNRTIs (efavirenz, nevirapine, rilpivirine) bind reverse transcriptase directly. Efavirenz causes CNS effects and vivid dreams. - Protease inhibitors (-navir, e.g., ritonavir, darunavir) cause hyperglycemia, lipodystrophy, and GI intolerance. Ritonavir is a CYP450 inhibitor and is used as a booster. - INSTIs (-gravir, e.g., dolutegravir, raltegravir) block integrase. They are generally well tolerated and are a first-line component. - Entry inhibitors: - Maraviroc blocks CCR5. - Enfuvirtide blocks gp41 fusion. - Ibalizumab binds CD4. - Pre-exposure prophylaxis (PrEP): tenofovir/emtricitabine or long-acting injectable cabotegravir or lenacapavir. Postexposure prophylaxis (PEP) is started within 72 hours and given for 28 days. - Perinatal prevention: maternal ART, and intrapartum IV zidovudine if viral load is high. Zidovudine prophylaxis for the neonate, and avoid breastfeeding in settings where safe alternatives are available. - Immune reconstitution inflammatory syndrome (IRIS) can occur after starting ART in patients with a latent or treated opportunistic infection.

**High-yield pearls** - HIV-2 is less virulent and is endemic in West Africa. It is intrinsically resistant to NNRTIs. - A rising viral load with a falling CD4 count suggests treatment failure or nonadherence. Check resistance genotyping. - Always screen for TB, hepatitis B and C, syphilis, and other STIs. Test HLA-B*5701 before abacavir. - If both TB and HIV are present, start TB treatment first. Start ART within about 2 weeks if CD4 is <50, otherwise within 8 weeks. Rifampin interacts with many ART agents. - For cryptococcal meningitis, delay ART for several weeks after starting antifungals.