Browsing by Author "Carrington, Mary"
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Item Open Access Common genetic variation and the control of HIV-1 in humans.(PLoS Genet, 2009-12) Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V; Colombo, Sara; Ledergerber, Bruno; Cirulli, Elizabeth T; Urban, Thomas J; Zhang, Kunlin; Gumbs, Curtis E; Smith, Jason P; Castagna, Antonella; Cozzi-Lepri, Alessandro; De Luca, Andrea; Easterbrook, Philippa; Günthard, Huldrych F; Mallal, Simon; Mussini, Cristina; Dalmau, Judith; Martinez-Picado, Javier; Miro, José M; Obel, Niels; Wolinsky, Steven M; Martinson, Jeremy J; Detels, Roger; Margolick, Joseph B; Jacobson, Lisa P; Descombes, Patrick; Antonarakis, Stylianos E; Beckmann, Jacques S; O'Brien, Stephen J; Letvin, Norman L; McMichael, Andrew J; Haynes, Barton F; Carrington, Mary; Feng, Sheng; Telenti, Amalio; Goldstein, David B; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.Item Open Access Determinants of protection among HIV‐exposed seronegative persons: an overview.(J Infect Dis, 2010-11-01) Lederman, Michael M; Alter, Galit; Daskalakis, Demetre C; Rodriguez, Benigno; Sieg, Scott F; Hardy, Gareth; Cho, Michael; Anthony, Donald; Harding, Clifford; Weinberg, Aaron; Silverman, Robert H; Douek, Daniel C; Margolis, Leonid; Goldstein, David B; Carrington, Mary; Goedert, James JBoth clinical experience and a growing medical literature indicate that some persons who have been exposed to human immunodeficiency virus (HIV) infection remain uninfected. Although in some instances this may represent good fortune, cohorts of uninfected persons have been reported who are considered at high risk for infection. In these cohorts a variety of characteristics have been proposed as mediating protection, but to date only the 32–base pair deletion in the chemokine (C‐C motif) receptor 5 gene, which results in complete failure of cell surface expression of this coreceptor, has been associated with high‐level protection from HIV infection. With this in mind, there are probably many other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. Because some of these factors are probably incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high‐risk uninfected cohorts, who should undergo targeted studies of plausible mediators and broad screening for unexpected determinants of protection.Item Open Access Host determinants of HIV-1 control in African Americans.(J Infect Dis, 2010-04-15) Pelak, Kimberly; Goldstein, David B; Walley, Nicole M; Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V; Gumbs, Curtis; Gao, Xiaojiang; Maia, Jessica M; Cronin, Kenneth D; Hussain, Shehnaz K; Carrington, Mary; Michael, Nelson L; Weintrob, Amy C; Infectious Disease Clinical Research Program HIV Working Group; National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (CHAVI)We performed a whole-genome association study of human immunodeficiency virus type 1 (HIV-1) set point among a cohort of African Americans (n = 515), and an intronic single-nucleotide polymorphism (SNP) in the HLA-B gene showed one of the strongest associations. We use a subset of patients to demonstrate that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide statistically significant association with viral load set point (P = 5.6 x 10(-10)). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant that influences viral load variation in African Americans, which is consistent with what has been observed for individuals of European ancestry, among whom the most important common variant is HLA-B*5701.Item Open Access Influence of HLA-C expression level on HIV control.(Science, 2013-04-05) Apps, Richard; Qi, Ying; Carlson, Jonathan M; Chen, Haoyan; Gao, Xiaojiang; Thomas, Rasmi; Yuki, Yuko; Del Prete, Greg Q; Goulder, Philip; Brumme, Zabrina L; Brumme, Chanson J; John, Mina; Mallal, Simon; Nelson, George; Bosch, Ronald; Heckerman, David; Stein, Judy L; Soderberg, Kelly A; Moody, M Anthony; Denny, Thomas N; Zeng, Xue; Fang, Jingyuan; Moffett, Ashley; Lifson, Jeffrey D; Goedert, James J; Buchbinder, Susan; Kirk, Gregory D; Fellay, Jacques; McLaren, Paul; Deeks, Steven G; Pereyra, Florencia; Walker, Bruce; Michael, Nelson L; Weintrob, Amy; Wolinsky, Steven; Liao, Wilson; Carrington, MaryA variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn's disease, suggesting a broader influence of HLA expression levels in human disease.Item Open Access KIR polymorphisms modulate peptide-dependent binding to an MHC class I ligand with a Bw6 motif.(PLoS pathogens, 2011-03) Colantonio, Arnaud D; Bimber, Benjamin N; Neidermyer, William J; Reeves, R Keith; Alter, Galit; Altfeld, Marcus; Johnson, R Paul; Carrington, Mary; O'Connor, David H; Evans, David TMolecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05(+) macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets.