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Title: Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome

Journal Article · · Retrovirology
 [1];  [1];  [1];  [2];  [3];  [3];  [3];  [4];  [5];  [5];  [1];  [1];  [1];  [1];  [6];  [7];  [6];  [5];  [8];  [9] more »;  [9];  [10];  [11] « less
  1. Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.; Santa Fe Inst. (SFI), Santa Fe, NM (United States)
  3. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Medicine
  4. Univ. of Alabama, Birmingham, AL (United States). Dept. of Medicine
  5. Univ. of Oxford (United Kingdom). Weatherall Inst. of Molecular Medicine
  6. Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery
  7. Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.; Duke Univ., Durham, NC (United States). Medical Center. Dept. of Pediatrics
  8. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.
  9. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Medicine; Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Microbiology
  10. Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.; Duke Univ., Durham, NC (United States). Medical Center. Dept. of Medicine; Duke Univ., Durham, NC (United States). Medical Center. Dept. of Immunology
  11. Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.; Duke Univ., Durham, NC (United States). Medical Center. Dept. of Medicine
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Background: A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method. Results: The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region. Conclusions: These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1626611
Journal Information:
Retrovirology, Vol. 9, Issue 1; ISSN 1742-4690
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English

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Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation journal November 2014
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A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies journal October 2017
HIV-1 Env C2-V4 Diversification in a Slow-Progressor Infant Reveals a Flat but Rugged Fitness Landscape journal April 2013
Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression journal August 2016
Immune camouflage: Relevance to vaccines and human immunology journal November 2014
Relative resistance of HIV-1 founder viruses to control by interferon-alpha journal January 2013
Quantification of Ebola virus replication kinetics in vitro journal November 2020
HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity journal March 2013
Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus journal July 2014
Kinetics of HIV-Specific CTL Responses Plays a Minimal Role in Determining HIV Escape Dynamics journal February 2018
Modelling and in vitro testing of the HIV-1 Nef fitness landscape journal July 2019
Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population journal December 2015
Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness journal January 2017
Transmission of Multiple HIV-1 Subtype C Transmitted/founder Viruses into the Same Recipients Was not Determined by Modest Phenotypic Differences journal December 2016
Interaction of the Host and Viral Genome and Their Influence on HIV Disease journal January 2019

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59 BASIC BIOLOGICAL SCIENCES
Virology
Human immunodeficiency virus type I
Viral fitness
Cytotoxic T lymphocytes
Immune escape mutation
Transmitted/founder virus
Mathematical model