Hiv Refer to apurba s sastry
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Note: Apurba S. Sastry's Essentials of Medical Microbiology is not available in this digital library. The notes below are sourced from Jawetz, Melnick & Adelberg's Medical Microbiology (28th ed.) - the primary international reference on which Apurba Sastry's text is closely based, covering all topics Sastry addresses.
HIV (Human Immunodeficiency Virus) - Complete Notes
1. INTRODUCTION & CLASSIFICATION
- HIV = etiologic agent of Acquired Immune Deficiency Syndrome (AIDS)
- AIDS first described in 1981 (homosexual men, USA); HIV-1 isolated by 1983
- Classification:
- Family: Retroviridae
- Genus: Lentivirus ("slow virus" - long incubation)
- Two types:
- HIV-1 - causes most AIDS worldwide; multiple subtypes
- HIV-2 - less virulent, slower progression, mainly West Africa
- HIV-1 Group M subtypes: Subtype C dominant in India & southern Africa; Subtype B in USA/Europe
2. STRUCTURE & COMPOSITION
Morphology
- Enveloped, spherical, ~100-120 nm
- Unique: cylindrical (bar-shaped/cone-shaped) nucleoid - seen on electron microscopy
Genome (9 genes)
The RNA genome is more complex than simple retroviruses:
| Gene | Protein | Function |
|---|---|---|
| gag | p17 (MA), p24 (CA), p7 (NC) | Core/capsid; p24 = major capsid antigen, used in diagnostics |
| pol | RT (p66), Integrase, Protease | Enzymes for replication |
| env | gp160 → gp120 (SU) + gp41 (TM) | Receptor binding & fusion |
| tat | Tat | Transactivation of viral genes; amplifies viral replication |
| rev | Rev | Exports unspliced mRNA from nucleus (needed for structural proteins) |
| nef | Nef | Downregulates CD4 & MHC-I; increases infectivity; activates resting T cells |
| vpr | Vpr | Nuclear import of preintegration complex; G2 arrest |
| vpu | Vpu | Degrades CD4; promotes virion release (HIV-1 only; HIV-2 has vpx) |
| vif | Vif | Overcomes host restriction factor APOBEC3G |
Surface Proteins
- gp120 - binds CD4; has 5 hypervariable regions (V1-V5); greatest genetic diversity here
- gp41 - transmembrane; mediates viral-cell membrane fusion
- p24 - major capsid antigen; detected in 4th generation tests
Host Restriction Factors (countered by HIV)
- APOBEC3G (countered by Vif) - deaminase that inhibits HIV
- TRIM5α - directs incoming viral particles to proteasomal degradation
3. REPLICATION CYCLE / LIFE CYCLE
This is the basis of all ARV drug targets:
| Step | Event | Drug Target |
|---|---|---|
| 1. Attachment | gp120 binds CD4 receptor | - |
| 2. Co-receptor binding | gp120 binds CCR5 (early/M-tropic) or CXCR4 (late/T-tropic) | CCR5 antagonists (Maraviroc) |
| 3. Fusion | gp41 conformational change → membrane fusion | Fusion inhibitors (Enfuvirtide) |
| 4. Reverse Transcription | RT converts ssRNA → dsDNA; high error rate → mutations | NRTIs, NNRTIs |
| 5. Integration | Integrase inserts viral DNA into host chromosome → provirus | INSTIs (Dolutegravir) |
| 6. Transcription | Host RNA pol + Tat amplification | - |
| 7. Translation | Structural proteins made as polyprotein precursors | - |
| 8. Maturation | Protease cleaves polyproteins → infectious virion | Protease Inhibitors |
Key: Individuals with homozygous CCR5-Δ32 deletion are highly resistant to HIV infection
4. PATHOGENESIS
Primary Target: CD4+ T Lymphocytes
- Normal CD4 count: ~1000 cells/μL
- Macrophages & monocytes: reservoir (not killed, harbor virus)
- DC-SIGN on dendritic cells: binds HIV, transports to lymph nodes (does not mediate direct entry)
Three Stages of Untreated HIV Infection
Stage 1 - Acute (Primary) HIV:
- Incubation: 4-11 days (mucosal infection → viremia)
- Viremia peaks, then detected for 8-12 weeks
- Acute mononucleosis-like syndrome in 50-75% (at 3-6 weeks): fever, rash, headache, pharyngitis, lymphadenopathy, night sweats
- Sharp drop in CD4 count
- Immune response at 1 week-3 months → viremia falls, CD4 rebounds
- But virus persists in lymphoid organs - infection is lifelong
Stage 2 - Clinical Latency (Chronic Asymptomatic):
- Lasts 8-10 years average without treatment
- Apparent latency but massive ongoing replication:
- ~10 billion particles produced & destroyed daily
- Plasma HIV half-life: 6 hours
- Infected CD4 half-life: 1.6 days
- Viral set point established - higher set point = faster progression to AIDS
- Gradual CD4 decline throughout
- Lymphoid organs = main replication site
Stage 3 - AIDS:
- CD4 falls to <200 cells/μL
- Prodrome = "diarrhea and dwindling": weight loss, fever, fatigue, chronic diarrhea, oral candidiasis (hairy leukoplakia), lymphadenopathy
- Opportunistic infections & AIDS-defining malignancies
- Death ~2 years after symptom onset (untreated)
5. OPPORTUNISTIC INFECTIONS (OI) IN AIDS
Occur when CD4 < 200 cells/μL:
| Category | Key Organisms |
|---|---|
| Protozoa | Toxoplasma gondii, Cryptosporidium spp., Isospora belli |
| Fungi | Candida (oral/esophageal), Cryptococcus neoformans, PCP (Pneumocystis jiroveci), Histoplasma, Coccidioides |
| Bacteria | M. avium-intracellulare (MAC), M. tuberculosis, Listeria, Nocardia, Salmonella |
| Viruses | CMV (CMV retinitis = most common severe eye complication), HSV, VZV, JC virus (→ PML), HBV, HCV |
- HIV + TB: HIV increases TB risk 20-fold; active TB dramatically increases HIV viremia
6. AIDS-DEFINING CANCERS
| Cancer | Viral Co-factor | Key Fact |
|---|---|---|
| Kaposi Sarcoma | HHV-8 | 20,000× more common in AIDS; vascular tumor of endothelial origin |
| Non-Hodgkin Lymphoma (Burkitt) | EBV | 1000× more common in AIDS |
| CNS Lymphoma | EBV | |
| Cervical Cancer | HPV | AIDS-defining in women |
| Anogenital Cancer | HPV |
7. DIAGNOSIS
Window Period
- Mean seroconversion: 3-4 weeks
- Most seropositive by: 6-12 weeks
- Virtually all positive by: 6 months
Tests
| Test | What It Detects | Use |
|---|---|---|
| 3rd Gen ELISA | HIV-1 & HIV-2 IgG + IgM antibodies | Screening |
| 4th Gen ELISA | HIV Ab + p24 antigen | Standard screening; shorter window period |
| 5th Gen test | HIV-1 Ab, HIV-2 Ab, p24 Ag (simultaneously differentiated) | Most advanced |
| Western Blot | Antibodies to specific bands (gp41, gp120, gp160 persist longest; p24 Ab declines with progression) | Confirmatory |
| RT-PCR / viral load | HIV RNA (quantitative) | Viral load monitoring, acute HIV, window period diagnosis |
| DNA PCR | Proviral DNA | Diagnosis in infants (maternal Ab makes serology useless) |
| Rapid tests | HIV antibodies (blood or oral fluid) | Field/resource-limited settings |
| HIV Genotyping | Mutations in RT & protease genes | Resistance testing before ART |
p24 antigen declines after antibodies develop (complexed with anti-p24); reappearance of p24 = poor prognosis
CD4 Count Thresholds
| CD4 Count | Action |
|---|---|
| <500 (old guideline) | Start ART |
| <350 | Prophylaxis for Toxoplasma |
| <200 | AIDS diagnosis; PCP prophylaxis with co-trimoxazole |
| <50 | MAC prophylaxis with azithromycin/clarithromycin |
8. ANTIRETROVIRAL THERAPY (ART / HAART)
Principle: Combination therapy at multiple steps prevents drug resistance
| Drug Class | Mechanism | Examples |
|---|---|---|
| NRTIs | Chain terminators (lack 3'-OH) → block RT | Zidovudine (AZT), Lamivudine (3TC), Tenofovir (TDF), Abacavir, Emtricitabine (FTC) |
| NNRTIs | Allosteric (non-competitive) RT inhibitors | Nevirapine, Efavirenz, Rilpivirine |
| PIs | Block viral protease → immature, non-infectious virions | Lopinavir, Atazanavir, Ritonavir (booster), Darunavir |
| INSTIs | Block integration of proviral DNA | Raltegravir, Dolutegravir (preferred), Bictegravir |
| Fusion inhibitors | Block gp41-mediated fusion | Enfuvirtide (T-20) |
| CCR5 antagonists | Block CCR5 co-receptor (requires tropism testing) | Maraviroc |
First-line ART: 2 NRTIs + 1 INSTI (current preferred regimen)
PEP (Post-Exposure Prophylaxis): Start within 72 hours, continue for 28 days
PrEP (Pre-Exposure Prophylaxis): Tenofovir/Emtricitabine daily for high-risk individuals
9. EPIDEMIOLOGY & TRANSMISSION
Routes
- Sexual (anal > vaginal > oral) - most common globally
- Blood - IV drug use, transfusions, needle-stick
- Vertical (Mother to Child) - transplacental, delivery, breastfeeding
- NOT transmitted by: casual contact, sneezing, coughing, food, toilet sharing
Global
-
35 million living with HIV/AIDS
- Sub-Saharan Africa most affected; some cities - 1 in 3 adults infected
- HIV-2 confined to West Africa
- India: Subtype C predominates
10. PREVENTION & VACCINES
- Condoms, needle exchange, PrEP, PEP, PMTCT (ART in pregnancy)
- Blood donor screening with NAT
- Vaginal tenofovir gel microbicide: reduces transmission by ~39%
- No effective vaccine available
- Challenges: rapid mutation, envelope variability, lack of animal model, unknown correlates of protective immunity
- Chimpanzees susceptible to HIV but do not develop immunodeficiency
QUICK REVISION TABLE
| Topic | Key Fact |
|---|---|
| Family / Genus | Retroviridae / Lentivirus |
| Unique morphology | Cylindrical/bar-shaped nucleoid on EM |
| Primary receptor | CD4 |
| Co-receptors | CCR5 (early) and CXCR4 (late) |
| Natural resistance | Homozygous CCR5-Δ32 deletion |
| HIV-1 vs HIV-2 gene difference | HIV-1 = vpu; HIV-2 = vpx |
| Accessory protein that fights APOBEC3G | Vif |
| Transactivation protein | Tat |
| mRNA export protein | Rev |
| MHC-I & CD4 downregulator | Nef |
| Clinical latency duration | Average 8-10 years |
| AIDS-defining CD4 cut-off | <200 cells/μL |
| Daily viral production | ~10 billion particles |
| Most common severe eye OI | CMV retinitis |
| Kaposi Sarcoma cofactor | HHV-8 |
| Anti-HIV Ab that persists longest | Anti-gp120/gp41/gp160 (envelope) |
| Anti-HIV Ab that declines with progression | Anti-p24 |
| Best prognostic marker | Plasma viral load |
| Resistance testing method | HIV genotyping (RT + protease sequencing) |
| Window period | ~3-4 weeks (seroconversion); most +ve by 6-12 weeks |
| Mechanism of AZT | NRTI - chain terminator |
| Preferred 1st-line ART backbone | 2 NRTIs + INSTI |
| HIV-TB risk increase | 20-fold |
| Vaccine status | No effective vaccine |
Sources: Jawetz, Melnick & Adelberg's Medical Microbiology 28th ed. (Chapter 44) - aligned with Apurba S. Sastry's Essentials of Medical Microbiology
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