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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 T24...

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Autores principales: Liu, Donglai, Zuo, Tao, Hora, Bhavna, Song, Hongshuo, Kong, Wei, Yu, Xianghui, Goonetilleke, Nilu, Bhattacharya, Tanmoy, Perelson, Alan S, Haynes, Barton F, McMichael, Andrew J, Gao, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264250/
https://www.ncbi.nlm.nih.gov/pubmed/25407514
http://dx.doi.org/10.1186/s12977-014-0101-0
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author Liu, Donglai
Zuo, Tao
Hora, Bhavna
Song, Hongshuo
Kong, Wei
Yu, Xianghui
Goonetilleke, Nilu
Bhattacharya, Tanmoy
Perelson, Alan S
Haynes, Barton F
McMichael, Andrew J
Gao, Feng
author_facet Liu, Donglai
Zuo, Tao
Hora, Bhavna
Song, Hongshuo
Kong, Wei
Yu, Xianghui
Goonetilleke, Nilu
Bhattacharya, Tanmoy
Perelson, Alan S
Haynes, Barton F
McMichael, Andrew J
Gao, Feng
author_sort Liu, Donglai
collection PubMed
description 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.
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spelling pubmed-42642502014-12-13 Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation Liu, Donglai Zuo, Tao Hora, Bhavna Song, Hongshuo Kong, Wei Yu, Xianghui Goonetilleke, Nilu Bhattacharya, Tanmoy Perelson, Alan S Haynes, Barton F McMichael, Andrew J Gao, Feng Retrovirology Research 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. BioMed Central 2014-11-19 /pmc/articles/PMC4264250/ /pubmed/25407514 http://dx.doi.org/10.1186/s12977-014-0101-0 Text en © Liu et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Liu, Donglai
Zuo, Tao
Hora, Bhavna
Song, Hongshuo
Kong, Wei
Yu, Xianghui
Goonetilleke, Nilu
Bhattacharya, Tanmoy
Perelson, Alan S
Haynes, Barton F
McMichael, Andrew J
Gao, Feng
Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation
title Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation
title_full Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation
title_fullStr Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation
title_full_unstemmed Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation
title_short Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation
title_sort preexisting compensatory amino acids compromise fitness costs of a hiv-1 t cell escape mutation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264250/
https://www.ncbi.nlm.nih.gov/pubmed/25407514
http://dx.doi.org/10.1186/s12977-014-0101-0
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