HIV/AIDS — Pathophysiology and Management

Causative agent

• HIV-1: lentivirus (retrovirus family) responsible for the global pandemic; group M subtypes predominate worldwide, subtype B in the United States
• HIV-2: largely West African, slower CD4 decline and lower transmissibility; intrinsically resistant to NNRTIs and enfuvirtide, so a stem describing an African patient failing efavirenz should prompt HIV-2 testing

Transmission grouped by mechanism

• Mucosal (sexual): virus crosses genital/rectal mucosa and is captured by dendritic cells; receptive anal intercourse carries the highest per-act risk because of thin columnar epithelium and rich submucosal CD4 targets
• Parenteral: shared injection equipment, transfusion in unscreened settings, occupational percutaneous exposure (roughly 0.3% per hollow-bore needlestick from a viremic source per CDC estimates)
• Vertical: in utero, intrapartum (the largest share), and via breastfeeding; risk tracks directly with maternal plasma viral load

Modifiable risk factors

• Condomless intercourse and multiple/concurrent partners: raises cumulative exposure
• Concurrent sexually transmitted infections: ulcerative disease (syphilis, HSV-2, chancroid) breaches epithelium and recruits activated CD4 cells to the mucosa — the classic "STI begets HIV" association
• Injection drug use and needle sharing: direct bloodstream inoculation
• Not using pre-exposure prophylaxis despite indication (USPSTF gives PrEP a grade A recommendation for persons at increased risk)
• High source viral load / untreated infection: an undetectable partner does not transmit sexually (U=U)
• Unsuppressed maternal viremia and breastfeeding where safe alternatives exist

Non-modifiable / host factors

• CCR5-Δ32 homozygosity: near-complete resistance to R5-tropic virus; heterozygotes progress more slowly
• Protective HLA class I alleles (*HLA-B\*57:01*, B\*27): stronger CD8 control, overrepresented among long-term nonprogressors; B\*57:01 also predicts abacavir hypersensitivity
• Perinatal exposure, age at infection, and regional prevalence: determine baseline exposure risk independent of behavior

Viral Entry and Replication Mechanisms

• CD4 and CCR5/CXCR4 receptor binding: HIV attaches to CD4 receptor on T helper cells, dendritic cells, and macrophages; requires co-receptor (CCR5 on macrophage-tropic R5 virus or CXCR4 on T-cell-tropic X4 virus) for membrane fusion and viral entry
• Reverse transcription: HIV reverse transcriptase converts viral RNA into DNA within the host cytoplasm, allowing integration into the host genome
• Integration into host genome: Viral integrase inserts HIV DNA into chromosome 9 (most common site), creating latent viral reservoirs that persist despite ART and complicate cure strategies
• Viral replication: Once integrated, HIV is transcribed and translated by host cell machinery, producing viral proteins and RNA; high viral turnover (10 billion virions/day at peak viremia)

CD4+ T Cell Destruction

• Direct cytopathic effects: Massive HIV replication within infected CD4+ cells leads to cell lysis, syncytia formation, and direct death
• Immune-mediated destruction: Antibody-dependent cellular cytotoxicity (ADCC) and CD8+ T cell killing of HIV-infected CD4+ cells accelerates depletion
• Thymic involution: HIV-induced damage to the thymus reduces generation of new CD4+ cells
• Lymphoid tissue damage: Progressive destruction of lymph node architecture impairs immune reconstitution

Immunosuppression and Opportunistic Infection Cascade

• CD4 <500 cells/μL: Loss of T cell help for B cells and macrophages; impaired delayed-type hypersensitivity; increased susceptibility to intracellular pathogens
• CD4 <200 cells/μL: Risk of Pneumocystis pneumonia (PCP), cryptosporidial diarrhea, and disseminated fungal infections
• CD4 <50 cells/μL: Risk of cytomegalovirus (CMV) retinitis, disseminated MAC (Mycobacterium avium complex), and cryptococcal meningitis
• Chronic immune activation: Persistent elevation of pro-inflammatory cytokines (TNF-α, IL-6) drives systemic inflammation, immune exhaustion, and increased risk of cardiovascular disease, malignancy, and accelerated aging

Viral Evolution and Drug Resistance

• High mutation rate: Reverse transcriptase lacks proofreading ability; ~1 mutation per 10,000 nucleotides synthesized generates escape variants
• Selection pressure: Incomplete adherence to ART allows resistant strains to outcompete wild-type virus

Acute Retroviral Syndrome (ARS)

• Fever, myalgia, arthralgia, and pharyngitis: Occurs 2-4 weeks post-infection in 40-80% of patients; mimics infectious mononucleosis or acute influenza
• Rash: Maculopapular rash on trunk and face (non-pruritic); appears in ~40% of ARS cases
• Lymphadenopathy: Generalized lymph node enlargement; CD4 count temporarily drops to 200-500 cells/μL then recovers
• Gastrointestinal symptoms: Diarrhea, nausea, vomiting; may reflect mucosal immune damage
• Neurologic involvement: Aseptic meningitis, Guillain-Barré syndrome (rarely); usually self-limited
• Clinical pearl: Many patients are seronegative at presentation (window period); diagnosis requires HIV RNA PCR (viral load test) rather than antibody serology

Chronic Asymptomatic Phase

• Often 8-10 years without symptoms if untreated; some patients have nonspecific symptoms (fatigue, weight loss, low-grade fever)
• CD4 count decline: Average decline is 50-100 cells/μL per year without treatment; rate varies by viral load and host genetics
• Persistent lymphadenopathy: Enlarged nodes (>1 cm) persisting >3 months in ≥2 sites outside inguinal region

AIDS-Defining Illnesses (CD4 <200 cells/μL if untreated)

• Infections: PCP (most common opportunistic infection in USA), candidal esophagitis, toxoplasma encephalitis, cryptococcal meningitis, CMV retinitis, MAC, tuberculosis (especially atypical presentations)
• Malignancies: Kaposi sarcoma (HHV-8), non-Hodgkin lymphoma (CNS lymphoma common in severe immunosuppression), cervical cancer
• Other: HIV encephalopathy, wasting syndrome (unexplained weight loss >10%)

Important Clinical Variants

• Long-term nonprogressors (LTNPs): CD4 remains >500 cells/μL for >10 years without ART; associated with protective HLA alleles and lower viral loads
• Acute manifestations during immune reconstitution: IRIS (immune reconstitution inflammatory syndrome) occurs within weeks of starting ART when CD4+ cells recover and mount inflammatory responses to previously uncontrolled opportunistic infections

Serologic Testing (Antibody-Based)

• 4th generation antigen/antibody test (recommended initial screening): Detects both HIV antibodies and p24 antigen; window period ~18 days
• Rapid tests: Produce results in minutes; used for point-of-care screening in clinics and ERs; sensitive but require confirmation with western blot or HIV RNA PCR
• Western blot: Gold standard confirmatory test; identifies specific antibodies against HIV proteins; takes 1-2 weeks

Virologic Testing

• HIV RNA PCR (viral load): Most sensitive test during acute infection (window period); measured in copies/mL; used to confirm diagnosis, assess prognosis, and monitor treatment efficacy
• HIV DNA PCR: Alternative confirmatory test; quantifies integrated viral DNA; less commonly used clinically
• Timing: If acute retroviral syndrome suspected and serology negative, use HIV RNA PCR for diagnosis

CD4 Count and Disease Staging

• CD4+ T cell count: Measured by flow cytometry; prognostic indicator and guide for opportunistic infection prophylaxis
• CD4 >500: Minimal OI risk
• CD4 200-500: Risk of PCP, toxoplasmosis, TB
• CD4 <200: High PCP risk; start trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis
• CD4 <50: Risk of MAC, CMV, cryptococcal meningitis; start MAC prophylaxis with azithromycin
• CD4 percentage: ≥29% on CD4 <500 cells/μL suggests better prognosis

Genotypic and Phenotypic Resistance Testing

• Baseline resistance testing: Performed at diagnosis to identify transmitted resistance
• On-treatment resistance testing: Performed if virologic failure occurs on ART
• Tropism assay: Determines CCR5 vs. CXCR4 usage; guides selection of maraviroc (CCR5 antagonist)

Additional Diagnostic Considerations

• Acute infection: May present with negative serology; diagnosis requires HIV RNA PCR
• Confirmation required: CDC guidelines require 4th generation antigen/antibody test followed by HIV-1/HIV-2 differentiation immun

Immediate priorities at diagnosis

• Start ART regardless of CD4 count or viral load: the HHS/NIH Panel on Antiretroviral Guidelines recommends ART for all persons with HIV, ideally same-day or rapid start, because early suppression preserves CD4 cells, shrinks the reservoir, and prevents transmission
• Baseline workup before or alongside first dose: genotypic resistance testing, HBV/HCV serologies, renal and hepatic function, pregnancy test, and *HLA-B\*57:01* typing if abacavir is contemplated
• Screen for active opportunistic infection first: in cryptococcal meningitis or TB meningitis, ART is deliberately deferred (typically several weeks) because immediate initiation increases IRIS-related mortality — treat the infection and control intracranial pressure first

First-line therapy (two NRTIs plus an integrase strand transfer inhibitor)

• INSTI backbone: bictegravir co-formulated with tenofovir alafenamide/emtricitabine, or dolutegravir plus tenofovir/emtricitabine (or lamivudine); high genetic barrier, few interactions, once-daily single tablet
• Pregnancy: dolutegravir-based regimens are now preferred by the HHS Perinatal Guidelines; intrapartum zidovudine is added when maternal viremia is not suppressed, and the neonate receives post-exposure prophylaxis

Escalation and second-line

• Confirmed virologic failure: repeat resistance testing while still on the failing regimen, then rebuild with at least two fully active drugs; boosted protease inhibitors (darunavir/ritonavir) offer the highest barrier to resistance
• Multidrug-resistant salvage: attachment/entry and capsid agents (fostemsavir, ibalizumab, lenacapavir) and maraviroc only if a tropism assay confirms R5 virus
• Long-acting injectable cabotegravir/rilpivirine: option for virologically suppressed patients with adherence barriers

Prophylaxis and prevention

• TMP-SMX for PCP when CD4 <200/μL or oropharyngeal candidiasis; also covers toxoplasmosis
• Azithromycin for MAC at CD4 <50/μL, though CDC/NIH opportunistic infection guidelines allow deferral when effective ART is started promptly
• PrEP and PEP: tenofovir/emtricitabine or long-acting cabotegravir for PrEP; occupational or sexual PEP is a three-drug regimen begun within 72 hours and continued 28 days

Contraindicated

• Monotherapy or dual-NRTI therapy — guarantees resistance
• **Abacavir with HLA-B\*57:01; NNRTIs in HIV-2**; tenofovir disoproxil with significant renal disease or osteoporosis

Opportunistic infections (disease-related)

• Pneumocystis jirovecii pneumonia: loss of CD4 help for alveolar macrophages; subacute dyspnea, hypoxia worsening with exertion, diffuse ground-glass infiltrates, elevated LDH. Add adjunctive corticosteroids when room-air PaO₂ is below 70 mmHg or the A–a gradient is ≥35 mmHg — respiratory failure here is an emergency
• Cryptococcal meningitis: encapsulated yeast triggers minimal inflammation; headache with markedly elevated opening pressure. Raised ICP is the killer — serial therapeutic lumbar punctures are as important as amphotericin B plus flucytosine (emergency)
• CMV retinitis at CD4 <50/μL: "pizza-pie" hemorrhagic retinitis; painless progressive vision loss is an ophthalmologic emergency
• Toxoplasma encephalitis: multiple ring-enhancing lesions with mass effect; herniation risk
• Progressive multifocal leukoencephalopathy (JC virus): non-enhancing white matter lesions, no mass effect, no specific therapy beyond ART

Malignancy

• Kaposi sarcoma (HHV-8), primary CNS lymphoma (EBV-driven, solitary periventricular enhancing lesion), systemic non-Hodgkin lymphoma, and HPV-driven cervical and anal cancer

Non-infectious chronic complications

• HIV-associated nephropathy: collapsing focal segmental glomerulosclerosis with heavy proteinuria and large echogenic kidneys
• Accelerated atherosclerotic cardiovascular disease from chronic immune activation, compounded by regimen-related dyslipidemia
• HIV-associated neurocognitive disorder: subcortical dementia with cerebral atrophy

Treatment-related

• IRIS: recovering CD4 cells unmask inflammation against residual antigen, typically within weeks of ART; paradoxical worsening of TB, cryptococcal, or MAC disease — CNS or airway IRIS is an emergency requiring corticosteroids while continuing ART
• Abacavir hypersensitivity: fever, rash, GI and respiratory symptoms in HLA-B\*57:01 carriers; rechallenge can be fatal (emergency)
• Tenofovir disoproxil: proximal tubular injury (Fanconi syndrome) and bone mineral density loss
• INSTIs and TAF: weight gain and metabolic drift; dolutegravir raises serum creatinine by blocking tubular secretion without lowering true GFR
• Protease inhibitors: insulin resistance, dyslipidemia, and CYP3A4-mediated interactions via ritonavir/cobicistat boosting
• Older NRTIs (stavudine, didanosine): mitochondrial toxicity — lactic acidosis with hepatic steatosis, peripheral neuropathy, lipoatrophy

• Acute retroviral syndrome with negative serology: the single best next step is HIV RNA PCR, not a repeat antibody test — the fourth-generation assay can still miss the earliest viremia. The common distractor is ordering a Western blot during the window period.
• Start ART in everyone, immediately: the HHS Panel no longer uses a CD4 threshold. A stem with a newly diagnosed asymptomatic patient and CD4 of 700 still gets ART. The exception examiners test is cryptococcal or TB meningitis, where ART is deferred to avoid fatal CNS IRIS.
• **Check HLA-B\*57:01 before abacavir**; once a hypersensitivity reaction occurs, the drug is never rechallenged. The same allele, confusingly, is associated with slower disease progression.
• Rising creatinine after starting dolutegravir is usually inhibition of tubular creatinine secretion, not renal injury — GFR is unchanged and the drug is continued. Contrast with tenofovir disoproxil, which causes true proximal tubular damage and Fanconi syndrome.
• CD4 thresholds drive prophylaxis: <200/μL → TMP-SMX for PCP (also covers toxoplasmosis); <50/μL → consider azithromycin for MAC, and think CMV retinitis in any patient with vision change at this level.
• Ring-enhancing brain lesions: multiple lesions favor toxoplasmosis (treat empirically with pyrimethamine-sulfadiazine and reimage); a solitary periventricular lesion with EBV DNA in CSF favors primary CNS lymphoma; non-enhancing white matter without mass effect is PML.
• Worsening symptoms weeks after starting ART with a rising CD4 and falling viral load is IRIS, not treatment failure — continue ART, treat the underlying infection, add steroids for severe or CNS disease.
• U=U: sustained virologic suppression eliminates sexual transmission, and dolutegravir-based ART is preferred in pregnancy per the HHS Perinatal Guidelines — the outdated distractor is withholding integrase inhibitors from pregnant patients.