Abstract
BackgroundDespite high potential for HIV-1 genetic variation, the emergence of some mutations is constrained by fitness costs, and may be associated with compensatory amino acid (AA) co-variation. To characterize the interplay between Cytotoxic T Lymphocyte (CTL)-mediated pressure and HIV-1 evolutionary pathways, we investigated AA co-variation in Gag sequences obtained from 449 South African individuals chronically infected with HIV-1 subtype C.Methodology/Principal FindingsIndividuals with CTL responses biased toward Gag presented lower viral loads than individuals with under-represented Gag-specific CTL responses. Using methods that account for founder effects and HLA linkage disequilibrium, we identified 35 AA sites under Human Leukocyte Antigen (HLA)-restricted CTL selection pressure and 534 AA-to-AA interactions. Analysis of two-dimensional distances between co-varying residues revealed local stabilization mechanisms since 40% of associations involved neighboring residues. Key features of our co-variation analysis included sites with a high number of co-varying partners, such as HLA-associated sites, which had on average 55% more connections than other co-varying sites.Conclusions/SignificanceClusters of co-varying AA around HLA-associated sites (especially at typically conserved sites) suggested that cooperative interactions act to preserve the local structural stability and protein function when CTL escape mutations occur. These results expose HLA-imprinted HIV-1 polymorphisms and their interlinked mutational paths in Gag that are likely due to opposite selective pressures from host CTL-mediated responses and viral fitness constraints.
Highlights
HIV is characterized by extensive genetic diversity, yet significant segments of the HIV-1 proteome are conserved across all subtypes [1], implying that there are limits to HIV variability: not all codons have been found to accept a mutation, and some replacements are only found in the presence of other mutations, exemplifying an evolutionary co-variation process among these amino acids (AA)
Our study focused on a previously described dataset [19,24] that included viral genomic sequences, Cytotoxic T Lymphocyte (CTL) response mapping, HLAtypes and clinical data from 598 treatment naıve, chronically infected individuals from KwaZulu-Natal in South Africa;,99% of them were infected with HIV-1 subtype C
Our results showed that CTL responses against Gag were fundamental to the control of viral replication in a cohort of HIV-1 subtype C infected individuals in KwaZulu-Natal, South Africa, and suggested that control of viremia was associated with the reduced variability of the Gag protein
Summary
HIV is characterized by extensive genetic diversity, yet significant segments of the HIV-1 proteome are conserved across all subtypes [1], implying that there are limits to HIV variability: not all codons have been found to accept a mutation, and some replacements are only found in the presence of other mutations, exemplifying an evolutionary co-variation process among these amino acids (AA).To assess co-variation robustly, Poon [2] and Carlson and their colleagues [3,4,5] developed phylogenetically-informed methods, which were designed to remove spurious associations stemming from shared ancestry and HLA linkage. A central tenet for assessing co-variation is the covarion principle, proposed by Fitch and Markowitz in 1970 [6], which states that ‘at any one point in time only a very restricted number of positions can fix mutations but that as mutations are fixed, the positions capable of accepting mutations change so that examination of a wide-range of species reveals a wide range of altered positions. We define this restricted group as the concomitantly variable codons [and] suggest the term ‘‘covarions’’ to describe this particular set of codons.’. To characterize the interplay between Cytotoxic T Lymphocyte (CTL)-mediated pressure and HIV-1 evolutionary pathways, we investigated AA co-variation in Gag sequences obtained from 449 South African individuals chronically infected with HIV-1 subtype C
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