Uncommon Pathways of Immune Escape Attenuate HIV-1 Integrase Replication Capacity

Abstract

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (n ‫؍‬ 88) and chronic (n ‫؍‬ 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R ‫؍‬ ؊0.2; P ‫؍‬ 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF 114 -121 ) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ϳ35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.

Impaired Nef Function Is Associated with Early Control of HIV-1 Viremia

“…In many cases, host expression of protective HLA alleles or the presence of specific HLA-associated escape mutations or both are associated with even lower viral protein function in these individuals, suggesting that adaptation to host HLA-restricted CTL can further attenuate HIV-1. Consistent with the observed "genetic fragility" (i.e., mutationally sensitive nature) of the HIV-1 p24 capsid protein as a result of its critical role in virion assembly (23), functional costs of CTL escape have been observed most readily in Gag (24)(25)(26)(27)(28), but immune-driven functional costs have also been demonstrated in Pol (18,29) and Env (19,30). The observation that compensatory mutations that offset the functional impact of escape arise more frequently in progressors than in controllers (28,31) (likely due in part to severely reduced viral replication in the latter individuals) further complicates the study of HIV-1 adaptation to its host and its pathogenic consequences.…”

Uneven Genetic Robustness of HIV-1 Integrase

“…One consideration is that CA would be predicted to be under greater immunological pressure than IN because Gag is expressed at 10-to 20-fold-higher levels than Pol in infected cells. While both IN and CA have been documented to be under selective pressure generated by host immune CD8 ϩ CTL responses, there is more evidence of CTL-imposed reductions in fitness in Gag/CA than in Pol/IN, suggesting the fragility exhibited by CA makes it particularly vulnerable to this type of pressure (86)(87)(88)(89)(90)(91). Thus, the similar degrees of natural sequence variation exhibited by IN and CA could simply reflect a similar balance of opposing forces, namely, immunological selective pressure (driving sequence diversification) and fragility (driving sequence conservation).…”

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

“…That the majority of HLA-associated polymorphisms occur outside known epitopes suggests that many epitopes remain undiscovered; indeed, HLA-associated polymorphisms represent an excellent tool to guide epitope discovery as they are unbiased by consensus sequences or limited knowledge of binding motifs (5,13,17,92). This study also extends our understanding of the proportion of population-level HIV-1 diversity attributable to HLA selection pressures, identifies abrogation of HLA-peptide binding as a predominant escape mechanism, suggests a potential evolutionary mechanism underlying differential escape between allele group members, and provides an extensive reference of proteome-wide HLA-mediated escape pathways.…”