HIV and AIDS

• Definition: HIV is a lentivirus that infects and depletes CD4+ T lymphocytes; AIDS is the clinical end-stage, defined by a CD4 count <200 cells/μL, CD4 percentage <14%, or the presence of an AIDS-defining condition regardless of CD4 count.
• Why it matters: untreated infection progresses over roughly a decade to profound cellular immunodeficiency and death from opportunistic infection or malignancy, whereas fully suppressive antiretroviral therapy (ART) yields a near-normal life expectancy. HIV is therefore the paradigm exam disease for linking a CD4 threshold to a specific pathogen.

Epidemiology worth recalling

• Burden: roughly 1.2 million people in the United States are living with HIV per CDC surveillance, and a substantial minority remain undiagnosed — the main driver of ongoing transmission.
• Who gets it: new US diagnoses are concentrated among men who have sex with men, and disproportionately affect Black/African American and Hispanic/Latino populations and the Southern states. Injection drug use and heterosexual contact account for most remaining cases.
• Transmission efficiency: using CDC per-act risk estimates, transfusion of infected blood carries by far the highest per-exposure risk (~9,250/10,000 acts). Among other exposures the hierarchy runs receptive anal intercourse (~138/10,000) > needle-sharing during injection drug use (~63/10,000) > percutaneous needlestick (~23/10,000) > insertive anal intercourse (~11/10,000) > receptive penile-vaginal intercourse (~8/10,000) > insertive penile-vaginal intercourse > mucosal splash. These point estimates carry wide confidence intervals and are modified by viral load, genital ulcer disease, and circumcision status.
• Perinatal transmission approaches zero with maternal viral suppression, which is why ACOG and the HHS perinatal panel recommend universal opt-out testing in pregnancy.
• Screening: the USPSTF gives a grade A recommendation for one-time screening of everyone aged 15–65 (and younger/older patients at increased risk), and for screening all pregnant patients.
• Global: sub-Saharan Africa carries most of the world's burden, where heterosexual and perinatal transmission predominate and tuberculosis is the leading cause of death.

Classification and structure

• Family/genus: Retroviridae, subfamily Orthoretrovirinae, genus Lentivirus — enveloped, with a conical (cone-shaped) p24 capsid surrounded by a p17 matrix, and a diploid genome of two identical copies of positive-sense single-stranded RNA (the only diploid human virus).
• HIV-1 vs HIV-2: HIV-1 group M causes the global pandemic; HIV-2 is largely West African, transmits less efficiently, progresses more slowly, and is intrinsically resistant to NNRTIs and enfuvirtide — a favorite distractor.

Genes and their products

• gag: p24 capsid and p17 matrix. p24 is the antigen detected by fourth-generation combination immunoassays.
• pol: reverse transcriptase (RNA-dependent DNA polymerase plus RNase H), integrase, and protease — the three enzymes packaged inside the virion and the three principal drug targets.
• env: gp160 cleaved by host protease into surface gp120 (receptor binding) and transmembrane gp41 (fusion).
• Accessory/regulatory genes: tat (transcriptional transactivator), rev (nuclear export of unspliced RNA), nef (downregulates surface CD4 and MHC I, aiding immune escape), plus vif, vpr, vpu.

Virulence and variability

• Error-prone reverse transcriptase lacks 3'→5' proofreading exonuclease activity, generating a quasispecies swarm — the mechanistic basis for rapid resistance and for why monotherapy fails.
• Envelope hypervariable loops and heavy glycosylation shield neutralizing epitopes.
• Tropism: R5 (CCR5-using, macrophage-tropic) strains dominate at transmission; X4 (CXCR4-using, T-cell-tropic, syncytium-inducing) variants emerge late and correlate with faster decline. Homozygous CCR5-Δ32 confers near-complete resistance to R5 strains.

Laboratory identification

• Not identified by Gram stain or routine culture; viral culture is a research technique only. Identification is serologic (antigen/antibody immunoassay, HIV-1/HIV-2 antibody differentiation) and molecular (RT-PCR for HIV RNA, genotypic resistance sequencing).

• Entry: gp120 binds CD4 on T-helper cells, macrophages, monocytes, and microglia; a conformational change exposes the co-receptor binding site for CCR5 or CXCR4, after which gp41 inserts its fusion peptide and merges the viral and cell membranes. Dendritic/Langerhans cells at the mucosa capture virions via DC-SIGN and ferry them to draining lymph nodes, seeding infection within days.
• Replication: reverse transcriptase makes double-stranded proviral DNA, integrase inserts it into host chromatin, and host RNA polymerase II transcribes progeny genomes. Protease cleaves Gag-Pol polyproteins during budding; without this step, virions are immature and non-infectious.
• Massive early GALT depletion: gut-associated lymphoid tissue holds the largest pool of activated CCR5+ memory CD4 cells, so the majority are destroyed within the first weeks. The resulting mucosal barrier injury permits microbial translocation, which drives chronic systemic immune activation — the engine of ongoing CD4 loss, accelerated atherosclerosis, and immune senescence even in treated patients.
• Mechanisms of CD4 death: direct cytolysis, syncytium formation between gp120-expressing and CD4-bearing cells, pyroptosis of abortively infected bystander cells, and CTL-mediated killing of infected cells.
• Latent reservoir: integrated provirus in resting memory CD4 cells and long-lived macrophages/microglia is transcriptionally silent, invisible to immune surveillance and unaffected by drugs that block active replication — the reason ART is lifelong and viremia rebounds within weeks of discontinuation.
• Consequences of CD4 loss: loss of Th1 help cripples macrophage activation and CD8 responses, explaining susceptibility to intracellular pathogens (Pneumocystis, Toxoplasma, mycobacteria, Cryptococcus, CMV) and to virus-driven cancers (HHV-8, EBV, HPV). Polyclonal B-cell activation produces hypergammaglobulinemia with paradoxically poor antigen-specific responses, so encapsulated bacterial infections also increase.
• Set point: post-acute viral load reflects the equilibrium between replication and CTL control and predicts rate of progression.

Stages

• Acute (Fiebig) stage: mononucleosis-like illness with very high viremia; patients are highly infectious. Antibody tests may still be negative.
• Clinical latency: often asymptomatic for years; persistent generalized lymphadenopathy may be the only finding, reflecting follicular hyperplasia in lymph nodes.

Syndromes by organ system (host risk factor = CD4 stratum)

• Pulmonary: Pneumocystis jirovecii pneumonia at CD4 <200 — subacute dyspnea, dry cough, hypoxia disproportionate to exam, diffuse bilateral perihilar infiltrates, elevated LDH. Tuberculosis occurs at any CD4 count but becomes atypical/disseminated with lower-lobe or miliary patterns as counts fall.
• Gastrointestinal: oral thrush and esophageal candidiasis (odynophagia with white adherent plaques on endoscopy; shaggy mucosa on barium swallow; AIDS-defining). Contrast the ulcer patterns: a solitary large ulcer → CMV esophagitis; multiple small punched-out/shallow ulcers → HSV esophagitis. CMV colitis and cryptosporidiosis (chronic watery diarrhea) occur at low counts. Oral hairy leukoplakia — EBV-driven, corrugated lateral tongue plaque that does not scrape off.
• Neurologic: toxoplasma encephalitis (multiple ring-enhancing lesions, basal ganglia/gray-white junction, mass effect); primary CNS lymphoma (EBV-associated, usually a solitary periventricular ring-enhancing lesion); PML from JC virus (multifocal non-enhancing white matter lesions without mass effect, progressive focal deficits); cryptococcal meningitis (indolent headache, fever, raised opening pressure); HIV-associated neurocognitive disorder with subcortical dementia.
• Ophthalmologic: CMV retinitis at CD4 <50 — painless progressive visual loss with hemorrhagic "pizza pie" retinitis.
• Disseminated: MAC at CD4 <50 with fever, night sweats, weight loss, cytopenias, and elevated alkaline phosphatase; histoplasmosis and coccidioidomycosis in endemic regions.
• Renal/derm: HIV-associated nephropathy — collapsing FSGS with heavy proteinuria and large echogenic kidneys, strongly linked to APOL1 risk variants in patients of West African ancestry; Kaposi sarcoma (HHV-8) as violaceous plaques on skin, palate, or viscera.

CDC/APHL laboratory algorithm (know this sequence)

• Step 1 — initial test: fourth-generation HIV-1/HIV-2 antigen/antibody combination immunoassay, which detects p24 antigen and antibody, shortening the window period to about 2–3 weeks. A negative result in a low-risk patient ends the workup.
• Step 2 — confirmation: a reactive screen reflexes to an HIV-1/HIV-2 antibody differentiation immunoassay, which both confirms infection and distinguishes HIV-1 from HIV-2 (this matters because HIV-2 is inherently NNRTI-resistant).
• Step 3 — discordance: if the differentiation assay is negative or indeterminate, perform an HIV-1 nucleic acid test (RNA). A positive NAT with negative antibodies indicates acute infection. Western blot is no longer part of the CDC algorithm — a classic outdated distractor.
• Suspected acute retroviral syndrome: order HIV RNA (or a combination assay) rather than antibody alone; RNA levels are typically in the hundreds of thousands to millions of copies/mL.
• Infants <18 months: transplacental maternal IgG makes serology uninterpretable — diagnose with HIV nucleic acid testing (DNA/RNA PCR) at defined intervals per the HHS perinatal guidelines.

Staging and baseline workup

• CD4 count stages disease and drives opportunistic-infection prophylaxis; AIDS = CD4 <200 cells/μL, CD4 <14%, or an AIDS-defining illness.
• Plasma HIV RNA (viral load) is the treatment-response measure, not a diagnostic staging tool.
• Genotypic resistance testing (reverse transcriptase/protease, with integrase testing when transmitted INSTI resistance is a concern) before starting ART.
• **HLA-B*5701** before abacavir to avoid a fatal hypersensitivity reaction; tropism assay only if maraviroc is contemplated.
• Co-infection and comorbidity screen: tuberculosis (IGRA/TST), hepatitis B and C serologies, syphilis, gonorrhea/chlamydia, Toxoplasma IgG, G6PD, pregnancy test, lipids and glucose, and cervical cancer screening.

Antiretroviral principles (HHS Panel on Antiretroviral Guidelines)

• Start ART immediately after diagnosis, at any CD4 count, and continue lifelong; the preferred backbone is an integrase strand transfer inhibitor plus two NRTIs. Never treat with fewer active drugs than a guideline-endorsed regimen — the error-prone reverse transcriptase selects resistance against monotherapy within weeks.
• Resistance patterns that change the choice: M184V (lamivudine/emtricitabine) also reduces viral fitness and partially resensitizes to zidovudine; K65R compromises tenofovir; K103N abolishes efavirenz/nevirapine but not etravirine; HIV-2 and NNRTIs do not mix. Baseline genotype and **HLA-B*5701** testing guide selection.
• Adverse effects tested: tenofovir disoproxil — renal tubular injury and bone loss (alafenamide is gentler); abacavir — hypersensitivity; protease inhibitors — dyslipidemia, hyperglycemia, and CYP3A4 interactions (ritonavir/cobicistat as pharmacokinetic boosters); dolutegravir — weight gain.
• U = U: sustained viral suppression eliminates sexual transmission.

Directed therapy for key opportunistic infections (CDC/NIH/IDSA)

• PCP: TMP-SMX is drug of choice; add adjunctive corticosteroids when room-air PaO₂ is <70 mmHg or the A–a gradient exceeds 35 mmHg. Alternatives include primaquine–clindamycin or atovaquone; check G6PD before primaquine/dapsone.
• Toxoplasma encephalitis: pyrimethamine + sulfadiazine + leucovorin (leucovorin prevents marrow suppression, and does not rescue the parasite).
• Cryptococcal meningitis: induction with liposomal amphotericin B plus flucytosine, then fluconazole consolidation, with serial lumbar punctures for elevated intracranial pressure.
• Disseminated MAC: a macrolide (azithromycin or clarithromycin) plus ethambutol.
• CMV retinitis: valganciclovir, with intravitreal therapy for sight-threatening lesions.

Prevention

• Primary prophylaxis: TMP-SMX at CD4 <200 (also covers Toxoplasma at CD4 <100 with positive IgG).
• PrEP (tenofovir/emtricitabine daily or long-acting injectable cabotegravir) and 28-day PEP after exposure.
• Vaccines: pneumococcal, hepatitis A/B, HPV, influenza, and Tdap; live vaccines are contraindicated when CD4 <200.

• A negative antibody test does not exclude acute HIV. In a patient 2–4 weeks out from exposure with fever, rash, and pharyngitis, the single best next step is an HIV RNA (or Ag/Ab combination) test, not a repeat antibody. p24 antigenemia precedes seroconversion.
• CD4 <200 with subacute dyspnea, dry cough, hypoxia out of proportion to exam, and elevated LDH = PCP. Start TMP-SMX, and add corticosteroids if PaO₂ <70 mmHg or A–a gradient >35 mmHg. Steroids in hypoxic PCP reduce mortality; withholding them is the classic missed point.
• Ring-enhancing brain lesions: multiple lesions in basal ganglia with mass effect → toxoplasmosis (empiric therapy, reassess in ~2 weeks); a solitary periventricular enhancing lesion → primary CNS lymphoma (EBV DNA in CSF); non-enhancing white matter lesions without mass effect → PML (JC virus, no specific antiviral — treat with ART).
• CD4 <50 club: CMV retinitis ("pizza pie" retina, painless vision loss) and disseminated MAC (fevers, weight loss, cytopenias, elevated alkaline phosphatase).
• IRIS is not treatment failure. Paradoxical worsening days to weeks after starting ART is managed with anti-inflammatories/steroids and by treating the unmasked pathogen — continue ART. The important exception in practice is cryptococcal meningitis, where ART is briefly delayed after antifungal induction.
• Never start ART as monotherapy or add a single drug to a failing regimen — the proofreading-deficient reverse transcriptase guarantees resistance. HIV-2 is intrinsically NNRTI-resistant.
• **Check HLA-B*5701 before abacavir**; check G6PD before dapsone or primaquine.
• Distractor to avoid: Western blot is no longer the confirmatory test — confirmation is the HIV-1/HIV-2 antibody differentiation immunoassay, with NAT to resolve discordance.

• Retrovirus with RNA genome; uses reverse transcriptase to integrate into host CD4+ T cell DNA
• CD4 count <200 cells/μL = AIDS diagnosis; normal CD4 is 500–1,500 cells/μL
• Three main transmission routes: sexual contact, blood exposure, mother-to-child
• Acute retroviral syndrome (ARS) occurs 2–4 weeks post-infection; often missed/misdiagnosed as flu
• Opportunistic infections (OIs) define AIDS when CD4 <200 cells/μL (PCP, toxoplasmosis, CMV, MAC, candidiasis)

Mnemonic—OIs by CD4

• <500: TB, Zoster, Candida
• <200: PCP (Pneumocystis), Toxo, Crypto
• <100: CMV, MAC

1. 1.Acute retroviral syndrome confused with flu/EBV—must have high suspicion; p24 antigen or RNA (not antibody) is positive early; antibodies develop in weeks to months
2. 2.Forgetting CD4 thresholds for OI prophylaxis—missed opportunities for TMP-SMX (PCP prophylaxis at <200) or fluconazole (candida at <50)
3. 3.Immune reconstitution inflammatory syndrome (IRIS)—occurs days to weeks after ART initiation when CD4 rapidly rises; presents as worsening of previously controlled OI (e.g., CMV uveitis)—treat with NSAIDs/corticosteroids, NOT by stopping ART

OI prophylaxis

• TMP-SMX for PCP when CD4 <200
• Fluconazole for candida when CD4 <50
• Azithromycin for MAC when CD4 <50