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

Journal Article · · PLoS Pathogens
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  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)
+ Show Author Affiliations

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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1201431
Journal Information:
PLoS Pathogens, Vol. 11, Issue 1; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 39 works
Citation information provided by
Web of Science

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Cited By (13)

Alterations of HIV-1 envelope phenotype and antibody-mediated neutralization by signal peptide mutations journal January 2018
Aiming for protective T-cell responses: a focus on the first generation conserved-region HIVconsv vaccines in preventive and therapeutic clinical trials journal October 2019
Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes journal June 2015
CD8+ T cells in HIV control, cure and prevention journal February 2020
Viral Characteristics Associated with the Clinical Nonprogressor Phenotype Are Inherited by Viruses from a Cluster of HIV-1 Elite Controllers journal April 2018
Role of HLA Adaptation in HIV Evolution journal January 2016
Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-α Resistance journal September 2015
Success and failure of the cellular immune response against HIV-1 journal May 2015
Identification of Immunodominant HIV-1 Epitopes Presented by HLA-C*12:02, a Protective Allele, Using an Immunopeptidomics Approach journal June 2019
Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness journal January 2017
HIV control: Is getting there the same as staying there? journal November 2018
A Naturally Occurring rev1-vpu Fusion Gene Does Not Confer a Fitness Advantage to HIV-1 journal November 2015
Composite Sequence–Structure Stability Models as Screening Tools for Identifying Vulnerable Targets for HIV Drug and Vaccine Development journal November 2015

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