Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis

• Type of Material: Article
• Authors: Daniel T. Claiborne, Emory University; Eileen P. Scully, Ragon Institute; Christine D. Palmer, Ragon Institute; Jessica L. Prince, Emory University; Gladys N. Macharia, International AIDS Vaccine Initiative; Jakub Kopycinski, International AIDS Vaccine Initiative; Clive M. Michelo, Zambia Emory HIV Research Project; Howard W. Wiener, University of Alabama Birmingham; Rachel Parker, Emory University; Krystelle Nganou-Makamdop, National Institute of Allergy and Infectious Diseases; Daniel Douek, National Institute of Allergy and Infectious Diseases; Marcus Altfeld, Heinrich Pette Institute; Jill Gilmour, International AIDS Vaccine Initiative; Matt A. Price, International AIDS Vaccine Initiative; Jianming Tang, University of Alabama Birmingham; William Kilembe, Zambia Emory HIV Research Project; Susan A Allen, Emory University; Eric Hunter, Emory University
• Language: English
• Date: 2019-08-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1007981
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 15
• Issue: 8
• Start Page: e1007981
• End Page: e1007981
• Grant/Funding Information: The full list of IAVI donors is available at http://www.iavi.org.; D.T.C. is supported by 5F32AI136750 from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health.; EH is a Georgia Eminent Scholar (gra.org).; E.P.S. is supported by K08AI116344 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health.; This work was funded in part by IAVI and made possible by the support of many donors, including United States Agency for International Development (USAID).; This study was funded by R01 MH095503-05 (SA), R01AI51231 and R01AI64060 (EH).; This work was also supported, in part, by the Virology Core at the Emory Center for AIDS Research by performing viral load determinations (grant P30 AI050409); the Yerkes National Primate Research Center base grant through the Office of Research Infrastructure Programs/OD P51OD11132.
• Keywords: MICROBIAL TRANSLOCATION; GUT; CD4+; SEX-DIFFERENCES; ESCAPE; PROGRESSION; DISEASE; Microbiology; Life Sciences & Biomedicine; Parasitology; RNA LEVELS; Science & Technology; T-CELL DEPLETION; ALCOHOL; Virology
• Research Categories: Biology, Parasitology; Biology, Virology

Abstract

Despite extensive research on the mechanisms of HLA-mediated immune control of HIV-1 pathogenesis, it is clear that much remains to be discovered, as exemplified by protective HLA alleles like HLA-B*81 which are associated with profound protection from CD4+ T cell decline without robust control of early plasma viremia. Here, we report on additional HLA class I (B*1401, B*57, B*5801, as well as B*81), and HLA class II (DQB1*02 and DRB1*15) alleles that display discordant virological and immunological phenotypes in a Zambian early infection cohort. HLA class I alleles of this nature were also associated with enhanced immune responses to conserved epitopes in Gag. Furthermore, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. Elevated LPS levels measured early in infection predicted accelerated CD4+ T cell decline, as well as immune activation and exhaustion. Taken together, these data suggest novel mechanisms for HLA-mediated immune control of HIV-1 pathogenesis that do not necessarily involve significant control of early viremia and point to microbial translocation as a direct driver of HIV-1 pathogenesis rather than simply a consequence.