A molecular basis for the control of preimmune escape variants by HIV-specific CD8+ T cells

Immunity. 2013 Mar 21;38(3):425-36. doi: 10.1016/j.immuni.2012.11.021.

Abstract

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigen Presentation / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Clone Cells / immunology
  • Clone Cells / metabolism
  • Clone Cells / virology
  • Crystallography, X-Ray
  • Epitopes, T-Lymphocyte / chemistry
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism
  • HIV Core Protein p24 / genetics
  • HIV Core Protein p24 / immunology
  • HIV Core Protein p24 / metabolism
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • HIV-1 / metabolism
  • HLA-B27 Antigen / chemistry
  • HLA-B27 Antigen / immunology*
  • HLA-B27 Antigen / metabolism
  • Humans
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / immunology
  • Immunodominant Epitopes / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Binding / immunology
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism

Substances

  • Epitopes, T-Lymphocyte
  • HIV Core Protein p24
  • HLA-B*27:05 antigen
  • HLA-B27 Antigen
  • Immunodominant Epitopes
  • Receptors, Antigen, T-Cell
  • p24 protein, Human Immunodeficiency Virus Type 1