Hiv in microbiology
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HIV in Microbiology
1. Classification
HIV belongs to:
- Family: Retroviridae
- Subfamily: Orthoretrovirinae
- Genus: Lentivirus ("lenti" = slow, reflecting the slow, progressive nature of disease)
- Types: HIV-1 (globally dominant) and HIV-2 (less virulent, mainly West Africa)
HIV-1 is further divided into groups M, N, O, and P. Group M contains the major pandemic clades (subtypes A-K), reflecting origin from chimpanzees (SIVcpz). HIV-2 derives from sooty mangabeys (SIVsm). - Harrison's Principles of Internal Medicine 22E, p.1601
2. Structure and Morphology
HIV is an icosahedral, enveloped RNA virus, approximately 100-120 nm in diameter.
Figure: Cross-section of HIV-1 - Harrison's Principles of Internal Medicine 22E
Key structural components:
| Component | Gene | Function |
|---|---|---|
| gp120 | env | Outer envelope glycoprotein; binds CD4 receptor |
| gp41 | env | Transmembrane; mediates membrane fusion |
| p24 | gag | Capsid protein; diagnostic antigen |
| p17 | gag | Matrix protein; inner membrane |
| p55 | gag | Gag polyprotein precursor |
| Reverse transcriptase | pol | Converts RNA → DNA |
| Integrase | pol | Integrates proviral DNA into host genome |
| Protease | pol | Cleaves polyprotein precursors |
The virion buds from the infected cell surface and incorporates host cell lipid bilayer proteins into its envelope. The envelope spikes exist as trimeric heterodimers of gp120-gp41. - Harrison's Principles of Internal Medicine 22E, p.1601
3. Genome
HIV has a diploid, single-stranded, positive-sense RNA genome (~9.7 kb), flanked by Long Terminal Repeats (LTRs) which contain regulatory elements.
Core genes (shared with all retroviruses):
- gag - encodes core structural proteins (matrix p17, capsid p24, nucleocapsid p7)
- pol - encodes enzymes: protease, reverse transcriptase (p66/p51), RNase H, integrase
- env - encodes envelope glycoproteins (gp160 → gp120 + gp41)
Regulatory/accessory genes (unique to HIV-1):
- tat - transactivates viral transcription (essential)
- rev - regulates export of unspliced mRNA from nucleus (essential)
- nef - downregulates CD4 and MHC class I expression; enhances viral replication
- vif - overcomes host restriction factor APOBEC3G
- vpr - nuclear import of preintegration complex; G2 cell cycle arrest
- vpu (HIV-1 only) - degrades CD4 in ER; enhances virion release
HIV-2 lacks vpu and instead has vpx, which degrades the restriction factor SAMHD1. - Harrison's Principles of Internal Medicine 22E, p.1602
4. Replication Cycle
The replication cycle proceeds through the following steps:
Step 1 - Attachment:
gp120 binds CD4 molecule (55-kDa protein, predominantly on T-helper lymphocytes) with high affinity.
Step 2 - Co-receptor binding:
gp120 undergoes conformational change and binds one of two major co-receptors:
- CCR5 (CC-chemokine receptor 5) - used by macrophage-tropic (M-tropic/R5) strains, predominant early in infection
- CXCR4 (CXC-chemokine receptor 4) - used by T-tropic (X4) strains, emerge later in disease
Both are seven-transmembrane-domain G protein-coupled receptors.
Step 3 - Fusion:
After co-receptor binding, gp41 is exposed and penetrates the target cell plasma membrane, folding upon itself to bring virion and host cell membranes together. Fusion occurs.
Step 4 - Uncoating and reverse transcription:
Capsid uncoating is initiated, forming the preintegration complex (viral RNA + enzymes + accessory proteins). As this complex traverses the cytoplasm toward the nucleus, reverse transcriptase (an error-prone enzyme with ~1 mutation per replication cycle) converts the single-stranded genomic RNA into double-stranded DNA (proviral DNA).
Step 5 - Nuclear import and integration:
The proviral DNA is transported into the nucleus, where integrase catalyzes its integration into the host chromosome, forming provirus. Latency begins.
Step 6 - Transcription and translation:
Host RNA polymerase II transcribes the provirus. Tat amplifies transcription. Rev shuttles unspliced mRNAs to the cytoplasm. Gag, Pol, and Env polyproteins are translated.
Step 7 - Assembly, budding, and maturation:
New virions assemble at the cell membrane and bud off. Protease cleaves the Gag and Pol polyproteins during or after budding, producing mature, infectious virions. - Harrison's Principles of Internal Medicine 22E, p.1601-1602
Key fact: Reverse transcriptase is error-prone and lacks proofreading activity, leading to ~1 mutation per virion per replication cycle. Every nucleotide of the HIV genome likely mutates on a daily basis across the viral population. - Jawetz Melnick & Adelbergs Medical Microbiology 28E, p.665
5. Cellular Tropism
| Cell Type | Co-receptor | Strain Type | Timing |
|---|---|---|---|
| CD4+ T lymphocytes | CXCR4 | T-tropic (X4) | Late infection |
| Monocytes/Macrophages | CCR5 | M-tropic (R5) | Early infection, predominant |
| Dendritic cells | DC-SIGN (binds gp120) | - | Facilitates spread to T cells |
| Microglial cells (brain) | CCR5 | M-tropic | Neuropathogenesis |
Individuals homozygous for the CCR5-Δ32 deletion are largely resistant to HIV-1 infection - a finding that led to the concept of the "Berlin Patient" cure via CCR5-null bone marrow transplant. - Jawetz Melnick & Adelbergs Medical Microbiology 28E
6. Natural History of Infection
Figure: Typical course of untreated HIV infection - Jawetz Melnick & Adelbergs Medical Microbiology 28E
Phases:
-
Primary (Acute) HIV infection (weeks 1-12): 4-11 day window before detectable viremia. 50-75% develop an acute mononucleosis-like syndrome (fever, rash, lymphadenopathy, pharyngitis) 3-6 weeks post-infection. Sharp drop in CD4 count. Plasma viremia is detectable 8-12 weeks.
-
Clinical Latency (months to ~10 years): CD4 count rebounds but virus continues replicating at a high rate (~10 billion particles produced and destroyed per day, viral half-life ~6 hours). CD4 count slowly declines. This phase is asymptomatic but infectious.
-
Symptomatic HIV / AIDS: As CD4 count falls:
- <500/μL: Constitutional symptoms, recurrent infections
- <200/μL: AIDS-defining illnesses (PCP, toxoplasmosis, CMV retinitis, cryptococcal meningitis)
- <50/μL: MAC (Mycobacterium avium complex), CMV disease
AIDS-defining malignancies: Kaposi sarcoma (HHV-8), non-Hodgkin lymphoma (EBV), invasive cervical carcinoma (HPV). - Jawetz Melnick & Adelbergs Medical Microbiology 28E, p.666
7. Viral Latency
A small fraction of infected CD4 T cells survive and revert to a resting memory state, forming a long-lived, stable latent reservoir. In this state, HIV gene expression is silenced (provirus integrated but not transcribed). This reservoir:
- Contains fewer than 1 cell per million resting CD4 T cells in treated patients
- Decays very slowly - would take ~70 years to clear with standard therapy
- Reactivates when memory cells are stimulated by antigen or when ART is stopped
This latent reservoir is the primary barrier to HIV cure. - Jawetz Melnick & Adelbergs Medical Microbiology 28E
8. Immunity
- Humoral: Antibodies to envelope glycoproteins (gp41, gp120, gp160) persist. Antibodies to Gag proteins (p24, p17) decline as disease progresses; loss of anti-p24 heralds disease progression.
- Cell-mediated: CD8+ cytotoxic T cells respond to HIV antigens, but cannot fully clear infection.
- Immune evasion: HIV mutates rapidly (quasispecies); dense glycosylation of gp120 shields neutralizing antibody epitopes; downregulates MHC I via Nef; depletes the very CD4+ T cells needed to coordinate the immune response.
9. Laboratory Diagnosis
| Test | Detects | Notes |
|---|---|---|
| 4th-generation EIA (Ag/Ab combo) | p24 antigen + HIV-1/2 antibodies | Standard initial test; window period ~18 days |
| 5th-generation assay | HIV-1 Ab, HIV-2 Ab, p24 Ag (differentiated) | Newer; differentiates HIV-1 from HIV-2 |
| Western blot / Immunoblot | HIV antibodies to specific proteins | Confirmatory test; bands at gp160, gp120, p24 |
| HIV RNA (viral load PCR) | HIV-1 RNA copies/mL | Detects acute infection; monitors treatment; window ~7-10 days |
| CD4 count | CD4+ T lymphocyte count | Staging; guides prophylaxis; normal >500/μL |
| HIV DNA PCR | Proviral DNA in cells | Used in neonates (maternal antibodies interfere with serology) |
| HIV Genotype Resistance Test | Mutations in RT and protease genes | Guides ART selection |
| Coreceptor tropism assay | CCR5 vs CXCR4 use | Required before prescribing CCR5 antagonists (maraviroc) |
Seroconversion: Mean time 3-4 weeks post-infection; virtually all seropositive by 6 months. - Jawetz Melnick & Adelbergs Medical Microbiology 28E, p.669-670
10. Antiretroviral Drug Targets
| Drug Class | Target | Examples |
|---|---|---|
| NRTIs | Reverse transcriptase (nucleoside analog) | Zidovudine, Tenofovir, Emtricitabine |
| NNRTIs | Reverse transcriptase (non-nucleoside) | Efavirenz, Nevirapine |
| Protease inhibitors (PIs) | Viral protease | Ritonavir, Lopinavir |
| Integrase inhibitors (INSTIs) | Integrase | Raltegravir, Dolutegravir, Bictegravir |
| Fusion inhibitors | gp41 | Enfuvirtide (T-20) |
| CCR5 antagonists | CCR5 co-receptor | Maraviroc |
| CD4 post-attachment inhibitor | CD4 molecule | Ibalizumab |
Current preferred regimens are 3-drug combinations (typically 2 NRTIs + 1 INSTI) known as ART (antiretroviral therapy). - Jawetz Melnick & Adelbergs Medical Microbiology 28E; Harrison's Principles of Internal Medicine 22E
Key Summary Points for Exams
- HIV-1 belongs to Lentivirus genus, Retroviridae family
- Hallmark enzyme: reverse transcriptase (RNA → DNA)
- Primary receptor: CD4 | Co-receptors: CCR5 (macrophage-tropic, early) and CXCR4 (T-tropic, late)
- AIDS is defined by CD4 count <200 cells/μL or an AIDS-defining illness
- 10 billion viral particles produced and destroyed daily during latency
- p24 antigen is the earliest detectable marker; viral RNA (PCR) has the shortest window period
- Latent reservoir in resting memory CD4 T cells is the main barrier to cure
- Nef downregulates CD4 and MHC-I; Vif overcomes APOBEC3G restriction; Tat is the transcriptional transactivator
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