Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4(+) T cells, and disease progression

• Type of Material: Article
• Authors: Daniel Claiborne, Emory University; Jessica Prince, Emory University; Eileen Scully, Ragon Institute of MGH, MIT and Harvard; Gladys Macharia, International AIDS Vaccine Initiative; Luca Micci, Emory University; Benton Lawson, Emory University; Jakub Kopycinski, International AIDS Vaccine Initiative; Martin J. Deymier, Emory University; Thomas Vanderford, Emory University; Krystelle Nganou-Makamdop, National Institutes of Health; Zachary Ende, Emory University; Kelsie Brooks, Emory University; Jianming Tang, University of Alabama at Birmingham; Tianwei Yu, Emory University; Shabir Lakhi, Zambia–Emory HIV Research Project; William Kilembe, Zambia–Emory HIV Research Project; Guido Silvestri, Emory University; Daniel Douek, National Institutes of Health; Paul A. Goepfert, University of Alabama at Birmingham; Matthew A. Price, International AIDS Vaccine Initiative; Susan A. Allen, Zambia–Emory HIV Research Projec; Mirko Paiardini, Emory University; Marcus Altfeld, Ragon Institute of MGH, MIT and Harvard; Jill Gilmour, Ragon Institute of MGH, MIT and Harvard; Eric Hunter, Emory University
• Language: English
• Date: 2015-03-24
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: Freely available online through the PNAS open access option.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1421607112
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 1091-6490
• Volume: 112
• Issue: 12
• Start Page: E1480
• End Page: E1489
• Grant/Funding Information: This study is supported in part by the International AIDS Vaccine Initiative (IAVI) (S.A.A.), whose work is made possible by generous support from many donors, including the Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation, the UK Department for International Development, and the US Agency for International Development (USAID).; This work was also supported in part by the Virology Core at the Emory Center for AIDS Research (Grant P30 AI050409 from the NIAID, NIH), by the Yerkes National Primate Research Center Base Grant (2P51RR000165-51) through the National Center for Research Resources P51RR165, and by the Office of Research Infrastructure Programs/OD P51OD11132.; This study was funded by Grants R01 AI64060 and R37 AI51231 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIAID, NIH) (to E.H.).; The full list of IAVI donors is available www.iavi.org. D.T.C., M.J.D., and J.L.P. were supported in part by Action Cycling Fellowships. E.H. is a Georgia Eminent Scholar.
• Keywords: SURVIVAL; Multidisciplinary Sciences; SIV INFECTION; PERSISTENCE; MORTALITY; replicative capacity; ANTIRETROVIRAL THERAPY; Gag; CHRONIC VIRAL-INFECTION; HIV-1; AIDS; Science & Technology; immune activation; RESPONSES; Science & Technology - Other Topics; EXPRESSION; pathogenesis; VIRUS TYPE-1 INFECTION
• Research Categories: Health Sciences, Public Health; Health Sciences, Immunology

Abstract

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.