HIV/AIDS: Etiopathogenesis and mechanism of T-cell immunodeficiency

Definitions

• HIV: Human immunodeficiency virus, a lentivirus belonging to the retrovirus family.
• AIDS: Advanced stage of HIV infection with severe immune deficiency, resulting in opportunistic infections, malignancies, and neurologic disease.
• The major defect is progressive loss and dysfunction of CD4+ helper T cells, causing mainly cell-mediated immunodeficiency.
  Robbins & Kumar Basic Pathology, p. 235-240.

1. Etiology

Causative virus

• HIV-1: Most common worldwide and more virulent.
• HIV-2: Seen mainly in West Africa and India; disease progression is generally slower.

Structure and important viral components

• Two copies of single-stranded RNA
• p24 capsid antigen
• Enzymes:
  • Reverse transcriptase
  • Integrase
  • Protease
• Envelope glycoproteins:
  • gp120: attachment to host cell
  • gp41: fusion of viral envelope with host-cell membrane

• gag: core proteins, including p24
• pol: reverse transcriptase, integrase, protease
• env: gp160, which is cleaved into gp120 and gp41

2. Modes of transmission

1. Sexual transmission - most common route
2. Parenteral transmission - shared needles, transfusion of contaminated blood products, accidental needle-stick exposure
3. Vertical transmission - mother to child:
   • In utero
   • During delivery
   • Through breast milk

3. Pathogenesis: How HIV infects cells

Target cells

• CD4+ T helper cells - principal target
• Macrophages
• Dendritic cells
• Microglial cells in CNS

Viral entry: easy sequence

Coreceptors

Viral replication

1. Viral RNA enters the host cell.
2. Reverse transcriptase forms viral DNA from viral RNA.
3. Integrase inserts viral DNA into host genome as a provirus.
4. Host cell produces viral RNA and proteins.
5. New virions assemble and bud from the cell.
6. Protease cleaves viral polyproteins, producing mature infectious virions.

4. Course of HIV infection

A. Acute infection

• Occurs soon after exposure.
• Virus initially enters through mucosal surfaces or blood.
• Dendritic cells carry virus to lymph nodes.
• There is rapid viral multiplication and viremia.
• A very large number of memory CD4+ T cells are destroyed in gut-associated lymphoid tissue (GALT).
• The patient may develop a mononucleosis-like illness: fever, rash, lymphadenopathy, sore throat.
• Anti-HIV CD8+ cytotoxic T cells reduce viremia, producing a clinically latent phase.

B. Chronic phase / clinical latency

• Virus remains active in lymphoid tissues despite relatively low plasma viremia.
• Persistent immune activation occurs.
• CD4+ T-cell count gradually falls.
• Lymph nodes initially show follicular hyperplasia, then become exhausted and fibrotic.
• Eventually, compensatory production of T cells cannot keep pace with T-cell destruction.

C. AIDS

• Severe depletion of CD4+ T cells leads to:
  • Opportunistic infections
  • Chronic diarrhea and wasting
  • Certain cancers, especially Kaposi sarcoma and B-cell lymphomas
  • CNS disease

5. Mechanism of CD4+ T-cell depletion and immunodeficiency

A. Direct viral cytopathic effect - the main mechanism

• Viral replication within the cell
• Increased membrane permeability during viral budding
• Interference with host-cell protein synthesis by viral proteins
• Apoptosis or pyroptosis of infected cells

B. Formation of syncytia

• gp120 expressed on an infected cell binds CD4 receptors on nearby uninfected T cells.
• The cells fuse and form multinucleated giant cells called syncytia.
• Syncytia die rapidly.

C. Death of uninfected T cells due to chronic immune activation

• Activation-induced apoptosis
• Immune exhaustion
• Increased turnover and loss of T cells

D. Damage to lymphoid tissues

• Early follicular hyperplasia
• Persistent inflammation
• Fibrosis and disruption of lymph-node architecture
• Loss of normal sites required for T-cell survival and regeneration

E. Early loss of memory CD4+ T cells in mucosa

• Mucosal tissues contain many activated memory CD4+ T cells, which are highly susceptible to HIV.
• Massive early destruction occurs especially in the intestinal mucosa.
• This leads to poor immune responses against previously encountered antigens and impaired mucosal defense.

F. Functional defects in surviving T cells

• Reduced antigen-induced proliferation
• Reduced cytokine production
• Reduced Th1 response
• Defective intracellular signaling
• T-cell exhaustion

Why loss of Th1 cells matters

• Intracellular bacteria, especially mycobacteria
• Fungi
• Viruses
• Protozoa

6. Final common pathway of immunodeficiency

Loss of CD4+ T-helper cells causes:

Flowchart for exam

HIV enters through blood or mucosa
            ↓
gp120 binds CD4 + CCR5/CXCR4
            ↓
gp41-mediated fusion and viral entry
            ↓
Reverse transcription → integration as provirus
            ↓
Infection of CD4 T cells, macrophages and dendritic cells
            ↓
Early massive loss of mucosal memory CD4 T cells
            ↓
Persistent viral replication + chronic immune activation
            ↓
Direct killing + syncytia + apoptosis of uninfected cells
            ↓
Lymphoid tissue damage and reduced T-cell regeneration
            ↓
Progressive CD4 T-cell depletion and dysfunction
            ↓
Loss of cell-mediated immunity
            ↓
Opportunistic infections, tumors and AIDS

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