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Title: Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients

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 focusedmore » 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.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3] ;  [4] ;  [5] ;  [6] ;  [4] ;  [6] ;  [7] ;  [5] ;  [3] ;  [1] ;  [1] more »;  [2] ;  [1] ;  [8] « less
  1. Emory Univ., Atlanta, GA (United States)
  2. Univ. of Oxford, Oxford (United Kingdom)
  3. Univ. of Alabama, Birmingham, AL (United States)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  5. International AIDS Vaccine Initiative, London (United Kingdom). Human Immunology Lab.
  6. Univ. of Pennsylvania, Philadelphia, PA (United States)
  7. Project San Francisco, Kigali (Rwanda). Rwanda-Zambia HIV Research Project
  8. Vaccine Research Center, Bethesda, MD (United States)
Publication Date:
OSTI Identifier:
1201431
Type:
Accepted Manuscript
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES