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Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus

Journal Article · · PLoS ONE
 [1];  [2];  [3];  [4];  [4];  [2];  [5];  [5];  [4];  [6];  [2]
  1. Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.; DOE/OSTI
  2. Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.; Santa Fe Inst. (SFI), Santa Fe, NM (United States)
  4. Univ. of Oxford (United Kingdom). Weatherall Inst. of Molecular Medicine
  5. Univ. of Pennsylvania, Philadelphia, PA (United States). Depts. of Medicine and Microbiology
  6. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.
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Immune escape mutations that revert back to the consensus sequence frequently occur in newly HIV-1-infected individuals and have been thought to render the viruses more fit. However, their impact on viral fitness and their interaction with other immune escape mutations have not been evaluated in the background of their cognate transmitted/founder (T/F) viral genomes. To precisely determine the role of reversion mutations, we introduced reversion mutations alone or together with CD8+ T cell escape mutations in their unmodified cognate T/F viral genome and determined their impact on viral fitness in primary CD4+ T cells. Two reversion mutations, V247I and I64T, were identified in Gag and Tat, respectively, but neither had measurable effect on the fitness of their cognate T/F virus. The V247I and G248A mutations that were detected before and concurrently with the potent T cell escape mutation T242N, respectively, were selected by early T cell responses. The V247I or the G248A mutation alone partially restored the fitness loss caused by the T242N mutation. Together they could fully restore the fitness of the T242N mutant to the T/F level. These results demonstrate that the fitness loss caused by a T cell escape mutation could be compensated by preexisting or concurrent reversion and other T cell escape mutations. Our findings indicate that the overall viral fitness is modulated by the complex interplay among T cell escape, compensatory and reversion mutations to maintain the balance between immune escape and viral replication capacity.
Research Organization:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1627718
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 7 Vol. 9; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (5)

Transmission of Multiple HIV-1 Subtype C Transmitted/founder Viruses into the Same Recipients Was not Determined by Modest Phenotypic Differences journal December 2016
Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation journal November 2014
A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies journal October 2017
Patterns and rates of viral evolution in HIV-1 subtype B infected females and males journal October 2017
Immunologic and Virologic Mechanisms for Partial Protection from Intravenous Challenge by an Integration-Defective SIV Vaccine journal June 2017

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