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

Attenuation of 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 in early (N=88) and chronic (N=304) infection, and measured the in vitro RC of each. In contrast to previous studies for 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, 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 (HTDNGSNF114-121) that likely contributes to selection of S119R, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding S119R displayed ∼35% reduced function that was rescued by a single compensatory mutation at 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 in future vaccine strategies.