Accumulation of CTL Escape Variants in the last twenty years and HLA-driven Convergence of Viral Subtypes

DARIO A DILERNIA,; L LOURTAU,; L JONES,; M GOMEZ-CARRILLO,; G TURK,; C BAUTISTA,; J BENETUCCI,; M LOSSO,; P CAHN; H SALOMON.

Boston, Massachusetts, EE.UU

Conferencia; 15th Conference on Retroviruses and Opportunistic Infections; 2008

Introduction: Accumulation of CTL-escape variants leading to negative associations between an HLA allele and a consensus residue was proposed previously (JEM 201:891, 2005). Recently, founder effect was shown to account for several of these associations, suggesting that HLA-driven evolution of HIV could be not such a stronger force as it was initially thought (Science 315:1583, 2007). The aim of this study was to seek for evidence of HLA-driven evolution. Methods: Gag gene was sequenced over 302 samples from drug-naive patients between 1987 and 2006. Viral subtype was characterized as B in 37.1%, F in 47.9% and BF in 13.6%. HLA-A and B genes were genotyped for 108 of them. Associations with viral polymorphisms were assessed by using logistic regression models. Multiple comparison corrections were addressed by the BH method (q-values). Phylogeny correction was performed by parsimony trees: large dataset analysis by Sectorial Search, Tree Drifting, Ratchet and Tree Fusing (Cladistics 15: 415-428). Recombinant structures were removed in order to avoid confounding effects. Trend analysis was performed by Chi-squared test for trend and GLM Repeated Measures. Results: We identified 15 potential escape mutations (p <0.05; q <0.2), 9 were inside epitopes suggested by anchor motifs and prediction software, reducing the affinity of the epitope for the HLA. Three associations were negative: Mutations R30K, A83V, and S125N were significantly more frequent in the absence of A24, A02 and A01, respectively. Consensus Ala, Arg and Ser have always dominated either B or F subtype while they have increased in time (F 3,12 =16.04; p<0.001) in the subtype they do not dominate until becoming the most frequent residue (>50%). Significantly different behavior in time (F 3,21 =6.91; p=0.002) was observed for mutations identified through positive associations, which have remained in a low prevalence (<30%) and did not change over time (F 3,30 =1.33; p=0.284). Conclusions: The rise of polymorphisms from independent origin was related to an association with an HLA allele. These findings support hypothesis of HLA-driven selection as a force able to determine evolution of viral populations. In our study, the fact that these residues accumulated in one of both subtypes are also characteristics of the other subtype shows how this selection might be causing a convergence of viral subtypes to variants more capable of evading the immune response of the population where they circulate.