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

• Published in: Nature (London) Vol. 432; no. 7018; pp. 769 - 775
• Main Authors: Kiepiela, Photini, Leslie, Alasdair J., Honeyborne, Isobella, Ramduth, Danni, Thobakgale, Christina, Chetty, Senica, Rathnavalu, Prinisha, Moore, Corey, Pfafferott, Katja J., Hilton, Louise, Zimbwa, Peter, Moore, Sarah, Allen, Todd, Brander, Christian, Addo, Marylyn M., Altfeld, Marcus, James, Ian, Mallal, Simon, Bunce, Michael, Barber, Linda D., Szinger, James, Day, Cheryl, Klenerman, Paul, Mullins, James, Korber, Bette, Coovadia, Hoosen M., Walker, Bruce D., Goulder, Philip J. R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.12.2004; Nature Publishing; Nature Publishing Group
• Subjects: Africa, Southern; Antigens; Biological and medical sciences; Biological Evolution; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Epitopes, T-Lymphocyte - immunology; Evolution; Female; Fundamental and applied biological sciences. Psychology; Gene Frequency; Gene Products, nef - chemistry; Genomics; 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; Human immunodeficiency virus 1; Humanities and Social Sciences; Humans; Infant; letter; Leukocytes; Male; Microbiology; multidisciplinary; nef Gene Products, Human Immunodeficiency Virus; Pathogens; Peptides; Polymorphism, Genetic - genetics; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Science; Science (multidisciplinary); Viral Load; Virology; Africa, Southern; Immune response; HIV-1 virus; Retroviridae; Host agent relation; Lentivirus; Virus; Molecular evolution; HLA-A-Locus; Histocompatibility restriction; Human immunodeficiency virus; Class I histocompatibility antigen; HLA-B-Locus; Polymorphism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature03113

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 1 , 2 , 3 . 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 4 , 5 . 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 6 , 7 , 8 . 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.