Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA

Nature. 2004 Dec 9;432(7018):769-75. doi: 10.1038/nature03113.

Abstract

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.

MeSH terms

  • Africa, Southern
  • Biological Evolution*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Gene Frequency
  • Gene Products, nef / chemistry
  • HIV Infections / immunology*
  • HIV Infections / virology*
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • HIV-1 / physiology*
  • HLA-A Antigens / genetics
  • HLA-A Antigens / immunology
  • HLA-B Antigens / genetics
  • HLA-B Antigens / immunology*
  • Humans
  • Infant
  • Male
  • Polymorphism, Genetic / genetics
  • Viral Load
  • nef Gene Products, Human Immunodeficiency Virus

Substances

  • Epitopes, T-Lymphocyte
  • Gene Products, nef
  • HLA-A Antigens
  • HLA-B Antigens
  • nef Gene Products, Human Immunodeficiency Virus