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

Retrovirology

Feng Gao⁴  Andrew J McMichael³  Barton F Haynes²  Alan S Perelson⁵  Tanmoy Bhattacharya⁵  Nilu Goonetilleke¹  Xianghui Yu⁴  Wei Kong⁴  Hongshuo Song²  Bhavna Hora²  Tao Zuo⁴  Donglai Liu⁴ 

[1] Department of Microbiology, Immunology and Medicine, University of North Carolina at Chapel Hill, Chapel Hill 27599, NC, USA;Duke Human Vaccine Institute, Duke University Medical Center, Durham 27710, NC, USA;Weatherall Institute of molecular Medicine, University of Oxford, Oxford OX3 9DS, England, UK;National Engineering Laboratory For AIDS Vaccine, College of Life Science, Jilin University, Changchun 130012, Jilin, China;Theoretical Division, Los Alamos National laboratory, Los Alamos 87545, NM, USA

关键词: Reversion;    Transmitted/founder virus;    Cytotoxic T lymphocytes;    Compensatory mutation;    Immune escape mutation;    Fitness;    HIV-1;   

Others  :  1151996
DOI  :  10.1186/s12977-014-0101-0

 received in 2014-06-19, accepted in 2014-10-28,  发布年份 2014

【 摘 要 】

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 acids 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.

【 授权许可】

   
2014 Liu et al.; licensee BioMed Central Ltd.

【 图 表 】

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