HIV molecular biology and pathogenesis Flashcards
Why is HIV complex?
It enables both replication and persistence in an immunocompetent adult host.
It facilitates cross-species transmission.
When does the AIDS process begin?
After 10+ years, along with viraemia.
Why was HIV initially thought to be latent?
Long clinical asymptomatic phase.
Low viral levels in peripheral blood.
Viral replication in vitro only detected in activated T cells.
What did further studies reveal about HIV latency?
It exhibits clinical latency, not cellular latency.
Rapid turnover of virus & infected cells.
10¹⁰ virions are produced per day.
What happens during clinical latency?
More CD4 cells are killed than produced.
Lymph node destruction weakens immune response.
CD4 cells lose function before depletion.
Accumulation of viral variants overwhelms immune system.
Primary Infection Symptoms (Mononucleosis-like Syndrome)
Fever, malaise, rash.
Diarrhea, lymphadenopathy.
Clinical Latency Symptoms
Often no symptoms.
May include fatigue, weight loss, thrush, shingles.
CD4 Count <500 cells/μL - Opportunistic Infections
Protozoal: Toxoplasma gondii, Cryptosporidia.
Bacterial: Treponema pallidum, Mycobacterium avium.
Fungal: Pneumocystis jirovecii, Candida albicans.
Viral: CMV, HSV, Kaposi’s Sarcoma, HPV.
CD4 Count <200 cells/μL - Severe Infections
Protozoal: Toxoplasma gondii.
Bacterial: Mycobacterium avium intracellulare.
Fungal: Cryptococcus neoformans.
Viral: EBV lymphoma, anogenital carcinoma.
Direct Pathogenicity of HIV
AIDS Dementia Complex (ADC): Brain macrophages/glial cells infected.
Weight loss: Gut macrophages infected → diarrhea, malabsorption.
Lung replication: Pulmonary complications.
HIV Target Cell Types
Monocytes/Macrophages: Ingest pathogens, kill infected/tumor cells.
Dendritic cells: Capture antigen, activate T-cells.
Follicular dendritic cells: Trap extracellular virus.
HIV Cell Entry Process
gp120 binds to CD4 receptor.
Conformational change exposes co-receptor binding site.
gp41 fusion domain facilitates viral entry.
Early HIV Infection - R5 Viruses
Use CCR5 (β-chemokine receptor).
Non-syncytium inducing (NSI) – No cell fusion.
Replicates in primary T-cells/macrophages, NOT in transformed T-cells.
Late HIV Infection - X4 Viruses
Use CXCR4 (α-chemokine receptor).
Syncytium-inducing (SI) – Fuses cells.
Mutation in V3 loop of gp120.
What genetic mutation protects against HIV?
32bp deletion in CCR5 gene.
1% of white population homozygous (resistant).
15% heterozygous (partial protection).
Why don’t these individuals get infected with X4 viruses?
They still have CXCR4 genes, but early transmission is CCR5-dependent.
Role of CCR5 in HIV Transmission
Virus in early infection is homogeneous, macrophage-tropic.
Macrophages in urogenital/anal mucosa = entry point.
CCR5 highly expressed in these macrophages.
Role of DC-SIGN in HIV Infection
DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Non-integrin).
Binds ICAM-3 on T-cells.
Captures HIV envelope glycoprotein.
Virions remain infectious for days.
