title: Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients.
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.
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Yue
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Katja J
authors.initials: KJ
authors.lastname: Pfafferott
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, Alabama, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Baalwa
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Conrod
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Dong
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chui
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Claiborne
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prince
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, Alabama, United States of America.
authors.forename: Jianming
authors.initials: J
authors.lastname: Tang
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Ruy M
authors.initials: RM
authors.lastname: Ribeiro
authors.affiliation: Human Immunology Laboratory, International AIDS Vaccine Initiative, London, United Kingdom.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Cormier
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Rwanda-Zambia HIV Research Project, Project San Francisco, Kigali, Rwanda.
authors.forename: Etienne
authors.initials: E
authors.lastname: Karita
authors.affiliation: Human Immunology Laboratory, International AIDS Vaccine Initiative, London, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, Alabama, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Goepfert
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Allen
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D005260:Female; D056084:Genetic Fitness; D057809:HEK293 Cells; D015658:HIV Infections / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000635:transmission; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D011379:Prognosis; D013601:T-Lymphocytes / Q000276:immunology*; D019562:Viral Load / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D018984:Epitopes, T-Lymphocyte