What is the pathophysiology of Human Immunodeficiency Virus (HIV)?

Pathophysiology of HIV Infection

HIV infection is characterized by progressive depletion of CD4+ T lymphocytes through multiple mechanisms including direct viral cytotoxicity, apoptosis of uninfected bystander cells, and chronic immune activation, ultimately leading to immunodeficiency and increased susceptibility to opportunistic infections and malignancies. 1, 2

Viral Entry and Initial Infection

• HIV primarily targets cells expressing the CD4 receptor, including:

  • CD4+ T lymphocytes (primary target)
  • Monocytes/macrophages
  • Dendritic cells

• Viral entry requires:

  • Binding of viral envelope glycoprotein gp120 to CD4 receptor
  • Subsequent interaction with co-receptors (primarily CCR5 or CXCR4)
  • Fusion of viral and cellular membranes mediated by gp41

• CNS infection occurs early in the disease course, with HIV crossing the blood-brain barrier primarily via infected monocytes/macrophages ("Trojan horse" mechanism) 3, 4

Mechanisms of CD4+ T Cell Depletion

HIV causes CD4+ T cell depletion through multiple pathways:

1. Direct viral cytopathic effects:

   • Viral replication within infected cells
   • Formation of syncytia (multinucleated giant cells)
   • Disruption of cellular metabolism

2. Apoptosis of uninfected bystander cells (predominant mechanism):

   • Fas-mediated apoptosis during activation-induced cell death (AICD)
   • HIV proteins (Tat, gp120, Nef, Vpu) released from infected cells trigger apoptosis in uninfected cells
   • Dysregulation of cytokine production (overproduction of type-2 cytokines like IL-4, IL-10) 1, 5

3. Chronic immune activation:

   • Persistent viral replication
   • Microbial translocation across damaged gut mucosa
   • Increased T cell turnover and exhaustion

Viral Reservoirs and Persistence

• HIV establishes latent reservoirs in:

  • Resting memory CD4+ T cells
  • Macrophages (which generally aren't destroyed but serve as viral reservoirs)
  • CNS (microglial cells, astrocytes)
  • Lymphoid tissues

• Viral persistence mechanisms:

  • Integration of proviral DNA into host genome
  • Low-level replication in sanctuary sites
  • Immune evasion through viral mutation and recombination 2, 6

Systemic Effects and Disease Progression

1. Intestinal mucosal damage:

   • Massive depletion of gut-associated lymphoid tissue (GALT) CD4+ T cells
   • Breakdown of intestinal barrier
   • Microbial translocation driving systemic immune activation 3

2. CNS pathology:

   • HIV infection of CNS occurs early in disease course
   • Spectrum of neurocognitive disorders from asymptomatic impairment to HIV-associated dementia
   • Mechanisms include direct viral infection, inflammatory responses, and neurotoxic viral proteins (gp120, Tat)
   • Breakdown of the blood-brain barrier and depletion of gut-resident CD4+ T-cell populations 3, 4

3. Cardiovascular effects:

   • Accelerated atherosclerosis and increased cardiovascular risk
   • Driven by chronic inflammation, immune activation, endothelial injury, and disordered coagulation
   • Compounded by traditional risk factors and antiretroviral therapy effects 3

4. Renal manifestations:

   • HIV-associated nephropathy (HIVAN)
   • Direct infection of renal epithelial cells
   • Genetic predisposition (APOL1 gene variants in individuals of African ancestry) 3

Phases of HIV Infection

1. Acute infection:

   • High viral replication and dissemination to lymphoid tissues
   • Rapid decline in CD4+ T cells, particularly in gut mucosa
   • Flu-like symptoms in many patients

2. Clinical latency/chronic phase:

   • Sustained immune activation and viral replication
   • Gradual decline in CD4+ T cell count
   • Often asymptomatic for years

3. Advanced disease/AIDS:

   • Profound CD4+ T cell depletion (<200 cells/μL)
   • Failure of immune surveillance
   • Opportunistic infections and malignancies 6, 7

Genetic Factors Influencing Disease Progression

• Host genetic factors affecting susceptibility and progression:
  • CCR5-Δ32 mutation (resistance to infection)
  • HLA alleles (influence rate of disease progression)
  • APOL1 gene variants (increased risk of HIV-associated nephropathy) 3

Complications of Antiretroviral Therapy

• Metabolic abnormalities (dyslipidemia, insulin resistance)
• Hypersensitivity reactions (particularly with abacavir, nevirapine)
• Mitochondrial toxicity
• Tenofovir-associated proximal tubulopathy
• CNS toxicity (particularly with efavirenz) 3, 4

Understanding the complex pathophysiology of HIV infection has led to the development of targeted antiretroviral therapies and continues to inform strategies for prevention, treatment, and potential cure of HIV infection.