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Title: Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation

Background: Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses. Results: The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acidsmore » for the T242N mutation and other T cell escape mutations. Conclusions: Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.« less
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [3] ;  [3] ;  [4] ;  [5] ;  [5] ;  [2] ;  [6] ;  [1]
  1. Duke Univ. Medical Center, Durham, NC (United States). Duke Human Vaccine Institute; Jilin Univ., Jilin (China). National Engineering Lab. for AIDS Vaccine, College of Life Science
  2. Duke Univ. Medical Center, Durham, NC (United States). Duke Human Vaccine Institute
  3. Jilin Univ., Jilin (China). National Engineering Lab. for AIDS Vaccine, College of Life Science
  4. Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Microbiology, Immunology and Medicine
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.
  6. Univ. of Oxford, Oxford, England (United Kingdom). Weatherall Institute of Molecular Medicine
Publication Date:
OSTI Identifier:
1212418
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Retrovirology
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1742-4690
Publisher:
BioMed Central
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES HIV-1; fitness; immune escape mutation; compensatory mutation; cytotoxic T lymphocytes; transmitted/founder virus; reversion