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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

Replication kinetics of T cell escape mutants. Frequencies of mutations in the TW10 epitope or CypA binding loop were determined by comparing the longitudinal sequences to the T/F sequences for CH58 (a), CH470 (b), and CH40 (c). The days post screening are indicated. The T242N escape mutation and compensatory amino acids were introduced into the CH58 (d), CH470 (e), and CH40 (f) T/F viral genomes. The replication kinetics of the mutants and their corresponding T/F viruses were determined by measuring p24 concentrations in the cell culture supernatants. The amino acids associated with T cell escape at the position 242 are indicated in red while the amino acids associated with compensation of the fitness loss at the positions 219 and 247 are indicated in blue. Each virus was cultured in triplicate. Mean values ± standard deviations are shown.
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Fig1: Replication kinetics of T cell escape mutants. Frequencies of mutations in the TW10 epitope or CypA binding loop were determined by comparing the longitudinal sequences to the T/F sequences for CH58 (a), CH470 (b), and CH40 (c). The days post screening are indicated. The T242N escape mutation and compensatory amino acids were introduced into the CH58 (d), CH470 (e), and CH40 (f) T/F viral genomes. The replication kinetics of the mutants and their corresponding T/F viruses were determined by measuring p24 concentrations in the cell culture supernatants. The amino acids associated with T cell escape at the position 242 are indicated in red while the amino acids associated with compensation of the fitness loss at the positions 219 and 247 are indicated in blue. Each virus was cultured in triplicate. Mean values ± standard deviations are shown.

Mentions: The T242N mutation was first detected 45 days post screening and was fixed in the viral population at day 350 in patient CH58 who was positive for HLA-B*57, which presents TW10 (Figure 1a), while it was not selected in CH470 and CH40 (Figure 1b and c), neither of which carry HLA-B*57/5801 alleles [3,4]. A G248E mutation was also detected at the same time when the T242N mutation occurred in CH58. However, it became undetectable while the T242N mutation was fixed in the viral population at day 350. Our previous study showed that the T242N mutation resulted in a significantly reduced T cell response while the G248E mutation only modestly affected T cell responses. The G248E mutation, however, abrogated binding of KIR3DL1 to HLA-B*5703, suggesting the emergence of this mutation was more likely associated with NK cell recognition [23]. Since the G248E was not clearly associated with T cell escape, it existed only transiently in the viral population, and the focus of the currently study was to determine fitness costs of the T242N mutation in different genetic backgrounds, the G248E mutation was not further studied.Figure 1


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)

Replication kinetics of T cell escape mutants. Frequencies of mutations in the TW10 epitope or CypA binding loop were determined by comparing the longitudinal sequences to the T/F sequences for CH58 (a), CH470 (b), and CH40 (c). The days post screening are indicated. The T242N escape mutation and compensatory amino acids were introduced into the CH58 (d), CH470 (e), and CH40 (f) T/F viral genomes. The replication kinetics of the mutants and their corresponding T/F viruses were determined by measuring p24 concentrations in the cell culture supernatants. The amino acids associated with T cell escape at the position 242 are indicated in red while the amino acids associated with compensation of the fitness loss at the positions 219 and 247 are indicated in blue. Each virus was cultured in triplicate. Mean values ± standard deviations are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Replication kinetics of T cell escape mutants. Frequencies of mutations in the TW10 epitope or CypA binding loop were determined by comparing the longitudinal sequences to the T/F sequences for CH58 (a), CH470 (b), and CH40 (c). The days post screening are indicated. The T242N escape mutation and compensatory amino acids were introduced into the CH58 (d), CH470 (e), and CH40 (f) T/F viral genomes. The replication kinetics of the mutants and their corresponding T/F viruses were determined by measuring p24 concentrations in the cell culture supernatants. The amino acids associated with T cell escape at the position 242 are indicated in red while the amino acids associated with compensation of the fitness loss at the positions 219 and 247 are indicated in blue. Each virus was cultured in triplicate. Mean values ± standard deviations are shown.
Mentions: The T242N mutation was first detected 45 days post screening and was fixed in the viral population at day 350 in patient CH58 who was positive for HLA-B*57, which presents TW10 (Figure 1a), while it was not selected in CH470 and CH40 (Figure 1b and c), neither of which carry HLA-B*57/5801 alleles [3,4]. A G248E mutation was also detected at the same time when the T242N mutation occurred in CH58. However, it became undetectable while the T242N mutation was fixed in the viral population at day 350. Our previous study showed that the T242N mutation resulted in a significantly reduced T cell response while the G248E mutation only modestly affected T cell responses. The G248E mutation, however, abrogated binding of KIR3DL1 to HLA-B*5703, suggesting the emergence of this mutation was more likely associated with NK cell recognition [23]. Since the G248E was not clearly associated with T cell escape, it existed only transiently in the viral population, and the focus of the currently study was to determine fitness costs of the T242N mutation in different genetic backgrounds, the G248E mutation was not further studied.Figure 1

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