Journal Article

The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation

Bernard, Nicole F, Alvino, Donna Marie L, Ribaudo, Heather J, Cutrell, Emily, Henn, Matthew R, Gianniny, Lauren, O'Leary, Jessica, Allen, Todd M, Barrie, William, Riddler, Sharon, Basgoz, Nesli, Bernard, Annette M, Boudreaux, Emilie T, Brown, Sheldon T, Guiducci, Candace, Bodner, Stanley J, Lemay, Paul, Beattie, Nicole, Shafer, Robert W, Bazner, Suzane, Qi, Ying, Kuritzkes, Daniel R, Brown, Katherine, Robbins, Gregory K, Deeks, Steven G, Bellos, Nicholaos C, Anderson, Ben, McLaren, Paul J, Ambardar, Sujata, Rosenberg, Rachel, de Bakker, Paul I W, Birch, Christopher, Berger, Judith, Gonzalez, Elena, Sax, Paul E, Basden, Patricia, Verma, Pranshu, Altschuler, Eric L, Graham, Robert R, Braun, James F, Agarwal, Shanu, Block, Brian, Antoniskis, Diana, Crenshaw, Andrew, Barbaro, Daniel, Andrady, Ushan, Rothchild, Alissa, Proudfoot, Jacqueline, Yuki, Yuko, Benson, Anne M, Bolan, Robert K, Gulick, Roy M, Walker, Bruce D, Ahern, Richard L, Anastos, Kathryn, Le Gall, Sylvie, Schaefer, Todd, Brndjar, Jon E, Addo, Marylyn M, Piechocka-Trocha, Alicja, Brown, Stephen J, Streeck, Hendrik, Jia, Xiaoming, Camargo, Amy, Toth, Ild

2010

Overview

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified > 300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alíeles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: AIDS / Alleles / Amino acids / Amino Acids - physiology / Antigen Presentation / Biological and medical sciences / Black or African American - genetics / CD8-Positive T-Lymphocytes - immunology / Classical genetics, quantitative genetics, hybrids / Cohort Studies / Disease Progression / Fundamental and applied biological sciences. Psychology / Genes, MHC Class I / Genetic effects / Genetics of eukaryotes. Biological and molecular evolution / Genome-Wide Association Study / Haplotypes / Hispanic or Latino - genetics / HIV / HIV Antigens - immunology / HIV Infections - ethnology / HIV Infections - genetics / HIV Infections - immunology / HIV Infections - virology / HIV Long-Term Survivors / HIV-1 - immunology / HLA antigens / HLA B antigens / HLA C antigens / HLA-A Antigens - chemistry / HLA-A Antigens - genetics / HLA-A Antigens - immunology / HLA-A Antigens - metabolism / HLA-B Antigens - chemistry / HLA-B Antigens - genetics / HLA-B Antigens - immunology / HLA-B Antigens - metabolism / HLA-C Antigens - chemistry / HLA-C Antigens - genetics / HLA-C Antigens - immunology / HLA-C Antigens - metabolism / Human / Human immunodeficiency virus 1 / Humans / Immunity, Innate / Infectious diseases / Logistic Models / Medical schools / Medical sciences / Models, Molecular / Molecular and cellular biology / Polymorphism, Single Nucleotide / Protein Conformation / Research universities / Viral diseases / Viral Load / White People - genetics