Paper I
Question
Pathogenesis of HIV infection and AIDS.
Answer
Virology
- HIV is a retrovirus (Lentivirus family) that primarily targets CD4+ T helper lymphocytes, along with macrophages and dendritic cells
Mechanism of entry
- The viral envelope glycoprotein gp120 binds to the CD4 receptor on the host cell, along with a chemokine co-receptor (CCR5 on macrophages, CXCR4 on T cells)
- This triggers conformational changes allowing gp41-mediated fusion of the viral envelope with the host cell membrane
Viral replication cycle
- Reverse transcriptase converts viral RNA to proviral DNA, which integrates into the host genome (via integrase)
- The integrated provirus can remain latent or be transcribed to produce new virions, which bud from the infected cell
Pathogenesis of CD4+ T cell depletion
- Direct cytopathic effect of viral replication on infected CD4+ cells
- Chronic immune activation leading to increased CD4+ T cell turnover and apoptosis (including of uninfected “bystander” cells)
- Destruction of lymphoid tissue architecture (especially gut-associated lymphoid tissue, an early and major site of CD4+ T cell depletion)
- Progressive decline in CD4+ count over years, compromising cell-mediated immunity
Clinical stages
- Acute retroviral syndrome: Transient flu-like illness at seroconversion, with high viral load
- Clinical latency (chronic phase): Years of relatively asymptomatic infection with ongoing viral replication and gradual CD4+ decline
- AIDS: CD4+ count falls below 200 cells/µL (or characteristic AIDS-defining opportunistic infections/malignancies develop) — profound immunodeficiency leads to opportunistic infections (Pneumocystis jirovecii pneumonia, CMV, tuberculosis, cryptococcal meningitis) and AIDS-defining malignancies (Kaposi sarcoma, non-Hodgkin lymphoma, invasive cervical carcinoma)