Abstract
BackgroundHLA class I-associated escape mutations in HIV-1 Gag can reduce viral replication, suggesting that associated fitness costs could impact HIV-1 disease progression. Previous studies in North American and African cohorts have reported reduced Gag-Protease mediated viral replication capacity (Gag-Pro RC) in individuals expressing protective HLA class I alleles including HLA-B*57:01, B*27:05, and B*81:01. These studies also reported significant positive associations between Gag-Pro RCs and plasma viral load (pVL). However, these HLA alleles are virtually absent in Japan, and the importance of Gag as an immune target is not clearly defined in this population.ResultsWe generated chimeric NL4-3 viruses carrying patient-derived Gag-Protease from 306 treatment-naive Japanese individuals chronically infected with HIV-1 subtype B. We analyzed associations between Gag-Pro RC and clinical markers of HIV-1 infection and host HLA expression. We observed no significant correlation between Gag-Pro RC and pVL in Japan in the overall cohort. However, upon exclusion of individuals expressing Japanese protective alleles HLA-B*52:01 and B*67:01, Gag-Pro RC correlated positively with pVL and negatively with CD4 T-cell count. Our results thus contrast with studies from other global cohorts reporting significantly lower Gag-Pro RC among persons expressing protective HLA alleles, and positive relationships between Gag-Pro RC and pVL in the overall study populations. We also identified five amino acids in Gag-Protease significantly associated with Gag-Pro RC, whose effects on RC were confirmed by site-directed mutagenesis. However, of the four mutations that decreased Gag-Pro RC, none were associated with reductions in pVL in Japan though two were associated with lower pVL in North America.ConclusionsThese data indicate that Gag fitness does not affect clinical outcomes in subjects with protective HLA class I alleles as well as the whole Japanese population. Moreover, the impact of Gag fitness costs on HIV-1 clinical parameters in chronic infection is likely low in Japan compared to other global populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0223-z) contains supplementary material, which is available to authorized users.
Highlights
human leukocyte antigen (HLA) class I-associated escape mutations in HIV-1 Gag can reduce viral replication, suggesting that associated fitness costs could impact HIV-1 disease progression
We investigated the effect of HLAassociated changes in Gag-Pro replication capacity (RC) in 306 treatment-naive HIV+ Japanese patients chronically infected with HIV-1 subtype B in the presence or absence of protective HLA alleles
In contrast to studies of nonAsian cohorts that supported a role of Gag fitness in HIV-1 disease outcome, our results suggested that Japanese protective alleles did not lower Gag-Pro RC and that Gag fitness did not correlate with clinical markers in the whole Japanese population
Summary
HLA class I-associated escape mutations in HIV-1 Gag can reduce viral replication, suggesting that associated fitness costs could impact HIV-1 disease progression. Previous studies in North American and African cohorts have reported reduced Gag-Protease mediated viral replication capacity (Gag-Pro RC) in individuals expressing protective HLA class I alleles including HLA-B*57:01, B*27:05, and B*81:01. These studies reported significant positive associations between Gag-Pro RCs and plasma viral load (pVL). The appearance of R264K in vivo generally heralds HIV-1 progression [23, 24] These studies support a relationship between Gag escape mutations and pVL and underscore a critical role of Gag in HIV-1 disease outcome
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