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The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation - pdf of published article attached
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Science Magazine
Nov 4 2010
The International HIV Controllers Study*  *All authors with their contributions and affiliations appear at the end of this paper.  To whom correspondence should be addressed. E-mail: (B.D.W.); (P.I.W.d.B.)
"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 analyzed the effects of individual amino acids within the classical HLA proteins. We identified >300 genome- wide significant 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 alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection."

"Altogether, these results link the major genetic impact of host control of HIV-1 to specific amino acids involved in presentation of viral peptides on infected cells. Moreover, they reconcile previously reported SNP and HLA associations with host control and lack of control to specific amino acid positions within the MHC class I peptide binding groove. Although variation in the entire HLA protein is involved in the differential response to HIV across HLA allotypes, the major genetic effects are condensed to the positions highlighted in this study, indicating a structural basis for the HLA association with disease progression likely mediated by the conformation of the peptide within the class I binding groove. The most significant residue, position 97 in the floor of the peptide binding groove of HLA-B, is associated with the most extremes of viral load depending on the expressed amino acid. This residue has been shown to have important conformational properties that impact epitope contacting residues within the binding groove (26, 30), and is also implicated in HLA protein folding and cell surface expression (31)."
"While the main focus of this study was on common sequence variation, it remains an open question as to the role of variants outside the MHC and the contribution of epistatic effects and epigenetic regulation. Additional factors also contribute to immune control of HIV, including fitness altering mutations, immunoregulatory networks, T cell help, thymic selection and innate effector mechanisms such as KIR recognition (23), some of which are influenced by the peptide-HLA class I complex. However, the combination and location of significant amino acids defined here are most consistent with the genetic associations observed being modulated by HLA class I restricted CD8+ T cells. These results implicate the nature of the HLA-viral peptide interaction as the major genetic factor modulating durable control of HIV infection and provide the basis for future studies of the impact of HLA-peptide conformation on immune cell induction and function."
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