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

Pathophysiology of HIV Infection

HIV infection causes progressive immune dysfunction primarily through CD4+ T-cell depletion and chronic immune activation, leading to immunodeficiency and increased risk of opportunistic infections and malignancies.

Viral Entry and Cellular Targets

HIV primarily targets cells expressing the CD4 receptor, including:

• Helper T lymphocytes (CD4+ T cells) - primary target
• Monocytes/macrophages - serve as viral reservoirs
• Dendritic cells
• Microglial cells in the brain

The infection process involves:

1. Binding of viral gp120 envelope protein to CD4 receptor
2. Secondary binding to co-receptors (CCR5 or CXCR4)
3. Fusion of viral and cellular membranes
4. Entry of viral contents into the cell
5. Reverse transcription of viral RNA to DNA
6. Integration of viral DNA into host genome
7. Viral replication and assembly

Mechanisms of Immune Destruction

HIV causes immune dysfunction through multiple mechanisms:

Direct Mechanisms:

• Direct cytopathic effects on infected CD4+ T cells 1
• Syncytia formation between infected and uninfected cells
• Viral proteins (particularly gp120) exert both stimulatory and suppressive effects on lymphocytes 2

Indirect Mechanisms:

• Chronic immune activation and inflammation 3
• Accelerated apoptosis of uninfected bystander cells
• Impaired T cell regeneration
• Destruction of lymphoid tissue architecture
• Host immune response against HIV-infected cells

Disease Progression

The natural history of untreated HIV infection typically follows these stages:

1. Acute infection:

   • High viral replication
   • Significant drop in CD4+ T cells
   • Flu-like symptoms
   • Widespread seeding of lymphoid tissues

2. Clinical latency:

   • Partial immune recovery
   • Ongoing viral replication despite apparent clinical stability
   • Gradual CD4+ T cell decline
   • Persistent immune activation

3. Advanced disease/AIDS:

   • CD4+ count <200 cells/μL
   • Emergence of opportunistic infections
   • Development of AIDS-defining malignancies
   • Neurological complications

Chronic Immune Activation

Chronic immune activation is a hallmark of HIV pathogenesis 3:

• Driven by:

  • Ongoing HIV replication
  • Microbial translocation from damaged gut mucosa
  • Reactivation of other viruses (CMV, EBV)
  • Homeostatic response to CD4+ depletion

• Consequences:

  • Exhaustion of immune cells
  • Accelerated immunosenescence
  • Fibrosis of lymphoid tissues
  • Increased risk of non-AIDS comorbidities

Clinical Manifestations

HIV infection leads to a wide range of clinical manifestations:

Opportunistic Infections:

• Pneumocystis pneumonia
• Tuberculosis
• Cryptococcal meningitis
• Toxoplasmosis
• Cytomegalovirus disease
• Disseminated Mycobacterium avium complex 4

Malignancies:

• Kaposi's sarcoma
• Non-Hodgkin lymphoma
• Primary CNS lymphoma 4
• Cervical cancer
• Anal cancer

Non-AIDS Complications:

• Cardiovascular disease
• Bone disease
• Renal and hepatic dysfunction
• Accelerated atherosclerosis
• Neurocognitive disorders 4, 5

Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS represents a paradoxical worsening of pre-existing infections after ART initiation:

• Occurs due to rapid restoration of immune responses against pathogens
• Common with tuberculosis, cryptococcosis, and other OIs
• Can cause significant morbidity and occasional mortality 4
• Typically occurs within weeks to months of ART initiation

Management Principles

Management of HIV infection focuses on:

1. Antiretroviral Therapy (ART):

   • Suppresses viral replication
   • Allows immune recovery
   • Prevents disease progression
   • Reduces transmission risk 5

2. Prophylaxis against opportunistic infections:

   • Based on CD4+ count thresholds
   • Prevents common opportunistic pathogens

3. Screening and management of comorbidities:

   • Cardiovascular risk assessment
   • Bone density monitoring
   • Renal and hepatic function evaluation 4

4. Vaccination:

   • Pneumococcal vaccine
   • Influenza vaccine
   • HPV vaccine
   • Other age-appropriate vaccinations 4

Special Considerations

Long-term Non-progressors

• Maintain stable CD4+ counts without ART
• Demonstrate robust HIV-specific CD8+ T cell responses
• May have genetic factors conferring protection 3

Elite Controllers

• Maintain undetectable viral loads without ART
• Provide insights for vaccine development

Pitfalls in Management

• Failure to recognize IRIS as distinct from treatment failure
• Overlooking non-AIDS comorbidities in virologically suppressed patients
• Neglecting screening for opportunistic infections in late presenters
• Underestimating risk of certain infections (TB, pneumococcal disease) even at higher CD4 counts 4
• Drug-drug interactions between ART and medications for comorbidities

HIV pathophysiology is complex, involving both direct viral effects and dysregulation of the immune system. Understanding these mechanisms is crucial for optimizing treatment strategies and developing novel therapeutic approaches.