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

Liu D, Zuo T, Hora B, Song H, Kong W, Yu X, Goonetilleke N, Bhattacharya T, Perelson AS, Haynes BF, McMichael AJ, Gao F - Retrovirology (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. ldl198653@126.com.

ABSTRACT

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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Related in: MedlinePlus

The prevalence of the T cell escape mutations in T cell epitopes with or without compensatory amino acids. One sequence from each HIV-1 infected individual in the Los Alamos HIV-1 Sequence Database was analyzed for four well-studied T cell epitopes (TW10, TL9, KR11 and ISW9). Over 4000 sequences were analyzed for each epitope. The frequency of the sequences with the CTL escape mutations and the frequency of the CTL mutant sequences with and without the compensatory amino acids were determined for each CTL epitope.
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Fig5: The prevalence of the T cell escape mutations in T cell epitopes with or without compensatory amino acids. One sequence from each HIV-1 infected individual in the Los Alamos HIV-1 Sequence Database was analyzed for four well-studied T cell epitopes (TW10, TL9, KR11 and ISW9). Over 4000 sequences were analyzed for each epitope. The frequency of the sequences with the CTL escape mutations and the frequency of the CTL mutant sequences with and without the compensatory amino acids were determined for each CTL epitope.

Mentions: I247 is present in the vast majority (94%) of the circulating virus sequences in the Los Alamos HIV sequence database. Thus, the clinical benefits of the T242N escape mutation could be mitigated significantly since the predominance of the compensatory amino acid can readily counteract the fitness loss of the T242N escape mutants in those individuals, as shown in a recent study in which the high population-level frequency of compensatory mutations for T cell escape mutation in TW10 and KF9 epitopes were found associated with limited protective effect of the B*5801 allele [31]. The T242N mutation is present in 13% of viruses in the Los Alamos HIV sequence database (Figure 5), suggesting that the T242N CTL escape mutant is frequently transmitted and does not revert back quickly. Interestingly, the T242N mutation is almost exclusively (95%) found linked to Q219 and/or I247 in the database (Figure 5). Similar results were obtained for the escape mutations in three other CTL epitopes (TL9, KF11 and ISW9) for which the compensatory mutations were characterized [12,32-35] (Figure 5).Figure 5


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

Liu D, Zuo T, Hora B, Song H, Kong W, Yu X, Goonetilleke N, Bhattacharya T, Perelson AS, Haynes BF, McMichael AJ, Gao F - Retrovirology (2014)

The prevalence of the T cell escape mutations in T cell epitopes with or without compensatory amino acids. One sequence from each HIV-1 infected individual in the Los Alamos HIV-1 Sequence Database was analyzed for four well-studied T cell epitopes (TW10, TL9, KR11 and ISW9). Over 4000 sequences were analyzed for each epitope. The frequency of the sequences with the CTL escape mutations and the frequency of the CTL mutant sequences with and without the compensatory amino acids were determined for each CTL epitope.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4264250&req=5

Fig5: The prevalence of the T cell escape mutations in T cell epitopes with or without compensatory amino acids. One sequence from each HIV-1 infected individual in the Los Alamos HIV-1 Sequence Database was analyzed for four well-studied T cell epitopes (TW10, TL9, KR11 and ISW9). Over 4000 sequences were analyzed for each epitope. The frequency of the sequences with the CTL escape mutations and the frequency of the CTL mutant sequences with and without the compensatory amino acids were determined for each CTL epitope.
Mentions: I247 is present in the vast majority (94%) of the circulating virus sequences in the Los Alamos HIV sequence database. Thus, the clinical benefits of the T242N escape mutation could be mitigated significantly since the predominance of the compensatory amino acid can readily counteract the fitness loss of the T242N escape mutants in those individuals, as shown in a recent study in which the high population-level frequency of compensatory mutations for T cell escape mutation in TW10 and KF9 epitopes were found associated with limited protective effect of the B*5801 allele [31]. The T242N mutation is present in 13% of viruses in the Los Alamos HIV sequence database (Figure 5), suggesting that the T242N CTL escape mutant is frequently transmitted and does not revert back quickly. Interestingly, the T242N mutation is almost exclusively (95%) found linked to Q219 and/or I247 in the database (Figure 5). Similar results were obtained for the escape mutations in three other CTL epitopes (TL9, KF11 and ISW9) for which the compensatory mutations were characterized [12,32-35] (Figure 5).Figure 5

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, 27710, USA. ldl198653@126.com.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus