Transmitted Virus Fitness and Host T Cell Responses Collectively Define Divergent Infection Outcomes in Two HIV-1 Recipients

• Type of Material: Article
• Authors: Ling Yue, Emory University; Katja J. Pfafferott, University of Oxford; Joshua Baalwa, University of Alabama; Karen Conrod, University of Oxford; Catherine C. Dong, Emory University; Cecilia Chui, University of Oxford; Rong Rong, Emory University; Daniel Claiborne, Emory University; Jessica L. Prince, Emory University; Jianming Tang, University of Alabama; Ruy M. Ribeiro, Los Alamos National Laboratory; Emmanuel Cormier, International AIDS Vaccine Initiative; Beatrice H. Hahn, University of Pennsylvania; Alan S. Perelson, Los Alamos National Laboratory; George M. Shaw, University of Pennsylvania; Etienne Karita, Rwanda-Zambia HIV Research Project; Jill Gilmour, International AIDS Vaccine Initiative; Paul Goepfert, University of Alabama; Cynthia Derdeyn, Emory University; Susan Allen, Emory University; Persephone Borrow, University of Oxford; Eric Hunter, Emory University
• Language: English
• Date: 2015-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Yue et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1004565
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 11
• Issue: 1
• Start Page: e1004565
• End Page: e1004565
• Grant/Funding Information: Portions of this work were done under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396 and supported by NIH grants R01-AI028433, R01-OD011095 and UM1-AI100645.; PB received salary support from a Senior Jenner Fellowship and is a Jenner Institute Investigator.; DTC and JLP were supported in part by Action Cycling Fellowships.; This study was funded by R01 AI64060 (EH) and R37 AI51231 (EH) from the National Institute of Alergy and Infectious Diseases, National Institutes of Health, by the Grand Challenges in Global Health Program of the Bill and Melinda Gates Foundation (#37874) (GMS and PB) and a Marie Curie Incoming International Fellowship from the European Commission (298450) (KJP).; This work also was supported, in part, by the Virology Core at the Emory Center for AIDS Research (Grant P30 AI050409, NIAID, NIH), and in part by the Yerkes National Primate Research Center base grant (2P51RR000165-51), funded by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132.; Field costs were provided by the International AIDS Vaccine Initiative (SAA), made possible in part by the generous support of the American people through the United States Agency for International Development (USAID).
• Research Categories: Health Sciences, Immunology; Biology, Virology; Health Sciences, Pathology

Abstract

Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.