Browsing by Keyword "HIV-1 progression"
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Publication Evaluating the Impact of Functional Genetic Variation on HIV-1 Control(Oxford University Press, 2017-11) McLaren, Paul J; Pulit, Sara L; Gurdasani, Deepti; Bartha, Istvan; Shea, Patrick R; Pomilla, Cristina; Gupta, Namrata; Gkrania-Klotsas, Effrossyni; Young, Elizabeth H; Bannert, Norbert; Amo, Julia del; Gill, M John; Gilmour, Jill; Kellam, Paul; Kelleher, Anthony D; Sönnerborg, Anders; Wolinsky, Steven M; Zangerle, Robert; Post, Frank A; Fisher, Martin; Haas, David W; Walker, Bruce D; Porter, Kholoud; Goldstein, David B; Sandhu, Manjinder S; de Bakker, Paul I W; Fellay, Jacques; Swiss National Science Foundation; Swiss HIV Cohort Study; Harvard University (Estados Unidos); University of California, San Francisco (Estados Unidos); Unión Europea. Comisión Europea. 7 Programa Marco; Red de Investigación Cooperativa en Investigación en Sida (España); NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos); NIH - National Cancer Institute (NCI) (Estados Unidos); NIH - National Institute on Drug Abuse (NIDA) (Estados Unidos); NIH - National Institute of Mental Health (NIMH) (Estados Unidos); NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute on Deafness and Communication Disorders (NIDCD) (Estados Unidos)Background. Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. Methods. We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. Results. Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. Conclusions. These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.Publication Mechanisms of abrupt loss of virus control in a cohort of previous HIV controllers(American Society for Microbiology (ASM), 2019) Rosás-Umbert, Miriam; Llano, Anuska; Bellido, Rocío; Olvera, Alex; Ruiz-Riol, Marta; Rocafort, Muntsa; Fernández, Marco A; Cobarsi, Patricia; Crespo, Manel; Dorrell, Lucy; Del Romero, Jorge; Alcamí, José; Paredes, Roger; Brander, Christian; Mothe, Beatriz; Instituto de Salud Carlos III; Ministerio de Sanidad (España); Fundación para la Innovación y la Prospectiva en Salud en España; Unión Europea. Comisión EuropeaElite and viremic HIV controllers are able to control their HIV infection and maintain undetectable or low-level viremia in the absence of antiretroviral treatment. Despite extensive studies, the immune factors responsible for such exclusive control remain poorly defined. We identified a cohort of 14 HIV controllers that suffered an abrupt loss of HIV control (LoC) to investigate possible mechanisms and virological and immunological events related to the sudden loss of control. The in-depth analysis of these subjects involved the study of cell tropism of circulating virus, evidence for HIV superinfection, cellular immune responses to HIV, as well as an examination of viral adaptation to host immunity by Gag sequencing. Our data demonstrate that a poor capacity of T cells to mediate in vitro viral suppression, even in the context of protective HLA alleles, predicts a loss of viral control. In addition, the data suggest that inefficient viral control may be explained by an increase of CD8 T-cell activation and exhaustion before LoC. Furthermore, we detected a switch from C5- to X4-tropic viruses in 4 individuals after loss of control, suggesting that tropism shift might also contribute to disease progression in HIV controllers. The significantly reduced inhibition of in vitro viral replication and increased expression of activation and exhaustion markers preceding the abrupt loss of viral control may help identify untreated HIV controllers that are at risk of losing control and may offer a useful tool for monitoring individuals during treatment interruption phases in therapeutic vaccine trials.IMPORTANCE A few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as HIV controllers. We have studied HIV controllers who suddenly lose this ability and present with high in vivo viral replication and decays in their CD4+ T-cell counts to identify potential immune and virological factors that were responsible for initial virus control. We identify in vitro-determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1-expressing CD8+ T cells with a naive immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals, and it may offer an important tool to anticipate viral rebound in individuals in clinical studies that include combination antiretroviral therapy (cART) treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants.