HIV & AIDS

A high-yield, frequently tested topic spanning virology, immunology and clinical medicine. Mastering HIV means knowing the virus architecture, the immunologic collapse it produces, the laboratory algorithm for diagnosis, CD4-driven opportunistic infection (OI) prophylaxis, and modern HAART. This single topic reliably generates 2-4 NEET PG questions every year.

Definition & classification

HIV (Human Immunodeficiency Virus) is an enveloped, single-stranded, positive-sense, diploid RNA retrovirus belonging to the Lentivirus genus of the family Retroviridae. It causes a chronic progressive depletion of CD4+ T-helper lymphocytes, culminating in profound cellular immunodeficiency.

AIDS (Acquired Immunodeficiency Syndrome) is the end stage of HIV infection, defined (CDC) by either:

• CD4 count < 200 cells/µL (or CD4% < 14%), OR
• Presence of an AIDS-defining illness regardless of CD4 count.

Feature	HIV-1	HIV-2
Origin	Chimpanzee (SIVcpz)	Sooty mangabey (SIVsm)
Distribution	Worldwide (pandemic)	West Africa (Guinea-Bissau), parts of India
Virulence / transmissibility	High	Low
Disease progression	Faster	Slower, long latency
Vertical transmission	More efficient	Less efficient
Response to NNRTIs	Sensitive	Intrinsically resistant
Diagnostic note	Detected by standard kits	May be missed; needs HIV-2 specific assay

High-yield: HIV-2 is intrinsically resistant to NNRTIs (e.g., nevirapine, efavirenz) and to the fusion inhibitor enfuvirtide. This is a recurring single-best-answer fact.

Groups of HIV-1: M (Major — causes the pandemic), N, O, P. Within group M, subtype C predominates in India; subtype B predominates in the USA/Europe.

Structure of the virion

The virion is roughly spherical (~100-120 nm). Key components, working from outside in:

• Envelope (lipid bilayer) derived from host cell membrane, studded with glycoprotein spikes.
• gp120 (surface, SU): binds the host CD4 receptor and co-receptors. The V3 loop of gp120 determines co-receptor tropism and is the principal neutralising target.
• gp41 (transmembrane, TM): mediates fusion of viral and cell membranes. gp120 + gp41 derive from the env gene precursor gp160.
• Matrix protein p17 lines the inner envelope.
• Capsid (core) protein p24: the cone-shaped nucleocapsid; p24 antigen is the earliest detectable serologic marker and basis of 4th-generation assays.
• Nucleocapsid p7 binds the RNA.
• Two identical (+)ssRNA copies (diploid genome) plus the enzymes.

Three essential enzymes (carried within the virion):

Enzyme	Gene	Function	Drug target
Reverse transcriptase	pol	RNA → DNA (error-prone, no proofreading)	NRTIs, NNRTIs
Integrase	pol	Integrates proviral DNA into host genome	INSTIs (raltegravir)
Protease	pol	Cleaves gag-pol polyprotein into mature proteins	Protease inhibitors

Genes: Structural — gag (p24, p17, p7), pol (RT, integrase, protease), env (gp120, gp41). Regulatory — tat and rev (essential); accessory — nef, vif, vpr, vpu (vpx in HIV-2).

High-yield: gp120 → attachment to CD4 + co-receptor; gp41 → fusion/entry. p24 antigenaemia is the first lab marker; reverse transcriptase lacks proofreading, explaining HIV's high mutation rate and rapid resistance.

Pathophysiology & life cycle

Receptors: gp120 binds CD4 (on T-helper cells, macrophages, dendritic cells, microglia). A co-receptor is mandatory:

• CCR5 — used by R5 (macrophage-tropic) strains in early infection. The CCR5-Δ32 homozygous deletion confers near-complete resistance to HIV acquisition.
• CXCR4 — used by X4 (T-cell-tropic) strains in later disease; associated with faster decline.

Replication cycle (flow):

Attachment (gp120–CD4) → co-receptor binding (CCR5/CXCR4) → fusion (gp41) → uncoating → reverse transcription (RNA→dsDNA) → nuclear import & integration (integrase → provirus) → transcription/translation → assembly at membrane → budding → maturation (protease cleavage).

Immunopathogenesis: progressive loss of CD4+ cells occurs by direct cytopathic killing, syncytium formation, CTL-mediated lysis of infected cells, and apoptosis (bystander). Latent provirus in resting memory CD4 cells forms the reservoir that prevents cure. As CD4 falls, cell-mediated immunity collapses, opening the door to opportunistic infections and malignancies.

High-yield: CCR5 is the early/macrophage-tropic co-receptor; maraviroc is the CCR5 antagonist (needs a tropism assay before use). CXCR4 use marks advanced disease.

Natural history & clinical features

1. Acute retroviral syndrome (2-4 weeks post-exposure): an infectious-mononucleosis-like illness — fever, pharyngitis, generalised lymphadenopathy, maculopapular rash, mucocutaneous ulcers, myalgia. High viraemia (very high viral load), transient CD4 dip. Antibodies are often not yet detectable (window period).

2. Clinical latency (asymptomatic, years): ongoing replication with gradual CD4 decline (~50-100 cells/µL/year untreated). Persistent generalised lymphadenopathy (PGL) may occur.

3. Symptomatic/AIDS: as CD4 < 200, OIs and malignancies appear.

WHO Clinical Staging (clinical, for resource-limited settings):

Stage	Representative features
Stage 1	Asymptomatic; persistent generalised lymphadenopathy
Stage 2	Weight loss <10%, recurrent respiratory infections, herpes zoster, seborrhoeic dermatitis, angular cheilitis
Stage 3	Weight loss >10%, chronic diarrhoea >1 month, oral candidiasis/hairy leukoplakia, pulmonary TB, severe bacterial infections
Stage 4 (AIDS)	HIV wasting, Pneumocystis pneumonia, oesophageal candidiasis, extrapulmonary TB, CNS toxoplasmosis, cryptococcal meningitis, CMV retinitis, Kaposi sarcoma, lymphoma, PML

CD4 count → opportunistic infections (very high-yield)

CD4 (cells/µL)	Characteristic infections/conditions
< 500	Oral/vaginal candidiasis, herpes zoster, TB, Kaposi sarcoma, oral hairy leukoplakia (EBV)
< 200	Pneumocystis jirovecii pneumonia (PCP), HIV-associated dementia
< 100	Toxoplasma encephalitis, cryptococcal meningitis, oesophageal candidiasis, chronic cryptosporidiosis
< 50	CMV retinitis, disseminated Mycobacterium avium complex (MAC), CNS lymphoma, PML

High-yield: CD4 < 200 = PCP risk; CD4 < 100 = Toxoplasma/Cryptococcus; CD4 < 50 = CMV + MAC. This staircase is asked almost every year.

Diagnosis & investigation of choice

HIV testing follows a screen-then-confirm algorithm.

Generations of assays:

• 1st gen: anti-HIV IgG (long window ~6-12 wk).
• 3rd gen: detects IgM + IgG (window ~3 wk).
• 4th gen (combo): detects p24 antigen + antibody — shortens window to ~2-3 weeks; current screening standard.

Classic algorithm: ELISA (screening, high sensitivity) → repeat reactive → Western blot / confirmatory (high specificity).

Western blot interpretation (commonly tested):

• Positive: reactivity to at least 2 of 3 key bands — p24, gp41, gp120/160 (criteria vary; CDC/WHO requires ≥2 bands).
• Indeterminate: some but insufficient bands → repeat in 4-6 weeks or use NAT.

Modern CDC algorithm (4th-gen): 4th-gen Ag/Ab combo → reactive → HIV-1/HIV-2 antibody differentiation immunoassay → if discordant/negative, HIV-1 RNA NAT. Western blot is now largely replaced by the differentiation assay in this scheme.

Investigation of choice:

• Screening: 4th-generation ELISA (p24 Ag + Ab).
• Confirmation (classic): Western blot.
• Earliest detection / window period / neonatal diagnosis: HIV RNA PCR (viral load / NAT) — detects within ~10 days, the earliest of all markers.
• Monitoring response to HAART: plasma HIV-1 RNA viral load (best marker of treatment efficacy).
• Monitoring immune status / when to start prophylaxis: CD4 count.

Window period: the interval between infection and detectability of the marker being used. p24 antigen and RNA appear earliest; antibodies take longer. With 4th-gen assays the practical window is ~2-3 weeks.

Infant diagnosis: maternal IgG crosses the placenta, so antibody tests are unreliable until 18 months. Use HIV DNA/RNA PCR at birth, 6 weeks, and later for definitive early diagnosis.

High-yield: In a neonate born to an HIV-positive mother, the diagnostic test of choice is HIV DNA PCR, NOT ELISA, because of transplacental maternal antibodies.

Order of marker appearance (flow)

HIV RNA (NAT) → p24 antigen → anti-HIV antibodies (ELISA/3rd-4th gen) → Western blot positivity.

This sequence explains why NAT closes the window earliest and why a recently infected patient can be antibody-negative but RNA/p24-positive.

Management — HAART / ART

Current principle: treat ALL HIV-positive patients regardless of CD4 count ("Test and Treat"). Start ART as early as possible; this both improves outcomes and reduces transmission (U=U: Undetectable = Untransmittable).

Drug classes & key examples:

Class	Mechanism	Examples	Signature toxicity
NRTIs	Chain terminators of RT	Tenofovir (TDF/TAF), lamivudine (3TC), abacavir, zidovudine (AZT), emtricitabine	Lactic acidosis; AZT → anaemia; TDF → renal/bone; abacavir → HLA-B*5701 hypersensitivity
NNRTIs	Non-competitive RT inhibition	Efavirenz, nevirapine, etravirine, rilpivirine	Efavirenz → CNS/neuropsychiatric; nevirapine → hepatotoxicity, rash/SJS
Protease inhibitors	Block protease maturation	Lopinavir, atazanavir, darunavir (boosted with ritonavir/cobicistat)	Metabolic syndrome, hyperlipidaemia, lipodystrophy; atazanavir → indirect hyperbilirubinaemia
Integrase inhibitors (INSTIs)	Block integrase	Dolutegravir, raltegravir, bictegravir	Weight gain; generally well tolerated
Entry/fusion inhibitors	Block entry	Enfuvirtide (gp41), maraviroc (CCR5)	Injection-site reactions (enfuvirtide)

High-yield: Standard first-line regimen (India NACO / WHO) = TDF + 3TC (or FTC) + Dolutegravir (TLD). Dolutegravir-based regimens are now preferred first-line globally for high efficacy and high resistance barrier.

Abacavir must NOT be given without checking HLA-B*5701, which predicts severe hypersensitivity.

Immune Reconstitution Inflammatory Syndrome (IRIS): paradoxical worsening of an existing/occult OI shortly after starting ART, due to recovering immunity. Most classic with TB and cryptococcal meningitis. Manage the underlying OI; continue ART; steroids in severe cases.

Opportunistic infection prophylaxis & treatment (drug of choice)

Condition	CD4 threshold to start prophylaxis	Drug of choice (prophylaxis)	Treatment DOC
Pneumocystis pneumonia (PCP)	< 200	Cotrimoxazole (TMP-SMX)	Cotrimoxazole (+ steroids if PaO₂<70)
Toxoplasmosis	< 100 (+ IgG positive)	Cotrimoxazole	Sulfadiazine + pyrimethamine + folinic acid
MAC	< 50	Azithromycin (clarithromycin)	Clarithromycin + ethambutol ± rifabutin
Cryptococcal meningitis	—	(pre-emptive if CrAg+)	Amphotericin B + flucytosine, then fluconazole
CMV retinitis	< 50	—	Ganciclovir/valganciclovir
TB	(any)	INH preventive therapy	Standard ATT (rifampicin interacts — use rifabutin with PIs)

High-yield: Cotrimoxazole is the single drug covering both PCP and Toxoplasma prophylaxis — start at CD4 < 200. Cryptococcal meningitis is diagnosed by India ink stain / CrAg latex agglutination, with raised CSF opening pressure; treat with amphotericin B + flucytosine induction.

Prevention of vertical (mother-to-child) transmission — PMTCT

Without intervention, vertical transmission is ~25-40%; with full PMTCT it falls to <1-2%. Transmission occurs in utero, intrapartum (highest risk), and via breastfeeding.

Strategy (flow): Maternal ART for life (start immediately, any CD4) → achieve undetectable viral load by delivery → mode of delivery guided by viral load (elective LSCS if VL >1000 copies/mL near term; vaginal delivery safe if suppressed) → infant antiretroviral prophylaxis (nevirapine ± zidovudine) → infant feeding counselling → HIV DNA PCR testing of infant.

High-yield: The biggest determinant of vertical transmission is the maternal viral load; suppressing it with ART is the single most effective intervention. Intrapartum is the period of highest transmission risk.

Post-exposure prophylaxis (PEP): start within 72 hours (ideally <2 h) of occupational/sexual exposure; 3-drug regimen (e.g., TDF + 3TC + dolutegravir) for 28 days. Pre-exposure prophylaxis (PrEP): oral TDF/FTC daily for high-risk HIV-negative individuals.

AIDS-defining illnesses & associated malignancies

• Infections: PCP, oesophageal candidiasis, CNS toxoplasmosis, cryptococcal meningitis, disseminated MAC, CMV retinitis, chronic cryptosporidiosis/isosporiasis, extrapulmonary TB, recurrent bacterial pneumonia, PML (JC virus).
• Malignancies: Kaposi sarcoma (HHV-8), non-Hodgkin & primary CNS lymphoma (EBV), invasive cervical carcinoma (HPV).
• HIV wasting syndrome and HIV encephalopathy.

High-yield: Kaposi sarcoma → HHV-8; primary CNS lymphoma & oral hairy leukoplakia → EBV; cervical cancer → HPV; PML → JC virus. Oral hairy leukoplakia is on the lateral tongue and does NOT scrape off (unlike candidiasis).

Complications

• Profound immunodeficiency → recurrent OIs (the principal cause of mortality untreated).
• HIV-associated neurocognitive disorder (HAND)/AIDS dementia complex.
• HIV nephropathy (FSGS — collapsing variant), commoner in subtype/ethnic groups with APOL1 risk alleles.
• Cardiovascular disease and metabolic syndrome (partly drug-related).
• IRIS after ART initiation.
• Drug toxicities and resistance from non-adherence.

Key differentials

• Acute retroviral syndrome mimics EBV/CMV infectious mononucleosis, secondary syphilis, acute viral hepatitis, and drug reaction — always consider HIV in a young patient with fever, rash, pharyngitis and lymphadenopathy; test with RNA/p24 because antibodies may be negative.
• CNS ring-enhancing lesion in AIDS: Toxoplasmosis (multiple lesions, basal ganglia) vs primary CNS lymphoma (single, periventricular, EBV-driven, thallium-SPECT/PET avid). Empirical anti-toxoplasma trial; if no response in 2 weeks → biopsy for lymphoma.
• Diarrhoea in AIDS: Cryptosporidium, Isospora, Microsporidia, MAC, CMV colitis.

Recently asked / exam angle

• Co-receptor pairing: gp120 binds CD4 + CCR5/CXCR4; gp41 mediates fusion — frequent image/diagram-based MCQs.
• Earliest serologic marker = p24 antigen; earliest overall = HIV RNA (NAT). Window-period questions recur every cycle.
• HIV-2 is NNRTI-resistant — single-best-answer favourite.
• CD4 thresholds for OI prophylaxis (200/100/50) and the matching drug of choice (cotrimoxazole for PCP + Toxo).
• Western blot bands (p24, gp41, gp120/160) and the ELISA→Western blot algorithm.
• First-line ART = TLD (Tenofovir + Lamivudine + Dolutegravir).
• Abacavir → HLA-B*5701 hypersensitivity testing.
• Infant diagnosis = HIV DNA PCR (not ELISA before 18 months).
• Best marker to monitor ART response = viral load (HIV RNA).
• IRIS most classically with TB and cryptococcal disease.
• Kaposi sarcoma — HHV-8; the most common AIDS-related malignancy.

Rapid revision

1. HIV = enveloped, diploid (+)ssRNA Lentivirus; reverse transcriptase has no proofreading → high mutation rate.
2. gp120 = attachment (CD4 + co-receptor); gp41 = fusion; p24 = capsid + earliest serologic marker.
3. Co-receptors: CCR5 (early, macrophage-tropic), CXCR4 (late); CCR5-Δ32 = resistance to acquisition; maraviroc = CCR5 antagonist.
4. HIV-2 is intrinsically NNRTI-resistant; subtype C predominates in India.
5. AIDS = CD4 < 200 OR an AIDS-defining illness.
6. OI staircase: <200 PCP, <100 Toxo/Crypto, <50 CMV/MAC.
7. Cotrimoxazole covers both PCP and Toxoplasma prophylaxis (start CD4 < 200).
8. Algorithm: ELISA screen → Western blot confirm; modern = 4th-gen Ag/Ab → differentiation assay → NAT.
9. Earliest test = HIV RNA PCR; infant diagnosis = DNA PCR (antibody unreliable <18 months); monitor ART with viral load.
10. First-line ART = TLD (TDF + 3TC + Dolutegravir); check HLA-B*5701 before abacavir.
11. PMTCT: maternal ART + suppressed viral load + infant prophylaxis cuts transmission to <1-2%; intrapartum is highest-risk window.
12. AIDS malignancies: Kaposi → HHV-8, CNS lymphoma → EBV, cervical cancer → HPV, PML → JC virus; PEP within 72 h, U = U.