What is the immune response to Human Immunodeficiency Virus (HIV)?

The Immune Response to HIV

The immune response to HIV is characterized by initial activation of innate and adaptive immunity followed by progressive immune dysfunction, with CD4+ T cell depletion as the hallmark feature leading to immunodeficiency and increased susceptibility to opportunistic infections and malignancies. 1

Initial Infection and Acute Phase

• Viral Entry and Target Cells:

  • HIV primarily targets cells expressing the CD4 receptor, including CD4+ T lymphocytes, monocytes/macrophages, and dendritic cells 1
  • Entry requires binding of viral envelope glycoprotein gp120 to CD4 receptor, followed by interaction with co-receptors (primarily CCR5 or CXCR4), and fusion mediated by gp41 1, 2

• Acute Immune Response:

  • Characterized by high viral replication and rapid decline in CD4+ T cells 1
  • Innate immune activation with production of inflammatory cytokines
  • Development of HIV-specific CD8+ cytotoxic T lymphocytes that initially help control viral replication 3
  • Early antibody responses that are typically not neutralizing or sustained 3

Chronic Infection and Immune Dysfunction

• Persistent Immune Activation:

  • Chronic immune activation is now recognized as a major driving force of CD4+ T cell depletion 4
  • Unlike natural SIV hosts that block immune activation and remain healthy, humans experience ongoing immune activation leading to immunosenescence and immunodeficiency 4

• Mechanisms of CD4+ T Cell Depletion:

  • Direct viral cytotoxicity
  • Host immune-mediated killing of infected cells
  • Destruction of uninfected "bystander" cells coated with viral gp120 3
  • Chronic immune activation leading to T cell exhaustion 4

• Immune Complex Formation:

  • Continuous formation of immune complexes in chronic infection
  • These complexes, along with TLR-ligands (viral antigens, bacterial products from damaged gut), interact with macrophages 5
  • This interaction transforms macrophages into type II activated forms that produce IL-10 and block IL-12, shifting away from effective Th1 responses 5

• Gastrointestinal Damage and Microbial Translocation:

  • Massive depletion of gut-associated lymphoid tissue CD4+ T cells
  • Breakdown of intestinal barrier leading to microbial translocation
  • Bacterial products entering bloodstream further drive systemic immune activation 1, 5

Viral Immune Evasion Mechanisms

• Antigenic Variation:

  • High mutation rate creates viral diversity that evades antibody and T cell responses 2, 6
  • Envelope structure minimizes antibody access to conserved regions 2

• Downregulation of MHC Molecules:

  • HIV downregulates MHC class I and II expression on infected cells
  • This reduces recognition by CD8+ T cells and impairs antigen presentation 2

• Establishment of Viral Reservoirs:

  • Macrophages serve as viral reservoirs without being destroyed 3
  • Latent infection of resting memory CD4+ T cells creates a persistent reservoir 1, 6
  • Early establishment of these reservoirs prevents viral eradication 7

Clinical Progression

• Three Stages of Disease:

  1. Acute infection: High viremia, CD4+ decline, flu-like symptoms
  2. Clinical latency: Sustained immune activation, gradual CD4+ decline, often asymptomatic for years
  3. Advanced disease/AIDS: Profound CD4+ depletion (<200 cells/mm³), opportunistic infections and malignancies 1

• Host Genetic Factors:

  • Certain genetic factors affect susceptibility and disease progression
  • CCR5-Δ32 mutation, specific HLA alleles, and APOL1 gene variants can influence outcomes 1

Implications for Treatment and Vaccines

• Treatment Goals:

  • Maximal suppression of viral load
  • Restoration and preservation of immune function
  • Reduction of HIV-related morbidity and mortality 7

• Vaccine Challenges:

  • Poor or unsustained protective immune responses to HIV
  • Need to balance beneficial versus potentially deleterious immune effects 3
  • Ongoing viral mutation and immune evasion mechanisms 2, 6

Understanding the complex interplay between HIV and the immune system remains essential for developing both preventive and curative therapies for HIV infection.