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Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection.

ABSTRACT: The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of low-frequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation.

SUBMITTER: Edwards CT

PROVIDER: S-EPMC1667091 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection.

Edwards C T T CT Holmes E C EC Pybus O G OG Wilson D J DJ Viscidi R P RP Abrams E J EJ Phillips R E RE Drummond A J AJ

Genetics 20060901 3

The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov ch ...[more]

PMID: 16951087

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Project description:BackgroundBiological monitoring of antiretroviral treatment (ART) in human immunodeficiency virus (HIV)-infected pediatric population remains challenging. The aim of the present study was to assess the long-term HIV-1 genetic diversity in pol gene in HIV-1-infected children in virological failure under antiretroviral regimen adapted according to the successive World Health Organization (WHO) guidelines for resource-constrained settings.MethodsHIV-1 diversity in pol gene was assessed in HIV-1-infected children and adolescents born from HIV-infected mothers (median age at follow-up: 13.8 years) in virological failure (VF+) despite long-term regimen recommended by the WHO. The numbers of nonsynonymous substitutions per potential nonsynonymous site (dN) and of synonymous substitutions at potential synonymous sites (dS) in HIV-1 pol gene and the dN/dS ratios were used to estimate the selective pressure on circulating HIV-1.ResultsThe immunological responses to ART basically corresponded to: 1) Full therapeutic failure with immunological (I-) and virological nonresponses in one-quarter (24.6%) of study children ((I-, VF+) subgroup); 2) Discordant immunovirological responses with paradoxical high CD4 T cell counts (I+) and high HIV-1 RNA load in the remaining cohort patients (75.4%) ((I+, VF+) subgroup). The mean dS was 1.8-fold higher in (I+, VF+) than (I-, VF+) subgroup (25.9 ± 18.4 vs. 14.3 ± 10.8). In the (I+, VF+) subgroup, the mean dS was 1.6-fold higher than the mean dN. Finally, the mean dN/dS ratio was 2.1-fold lower in (I+, VF+) than (I-, VF+) subgroup (0.6 ± 0.3 vs. 1.3 ± 0.7), indicating purifying selection in the immunovirological discordant (I+, VF+) subgroup and positive selection in the immunovirological failure (I-, VF+) subgroup.ConclusionsChildren and adolescents in immunovirological therapeutic failure harbor positive selection of HIV-1 strains favoring diversifying in pol-encoded amino acids. In contrast, children with persistent discordant immunovirological responses show accumulation of mutations and purifying selection in pol gene sequences, indicating limited genetic evolution and likely suggesting genetic adaptation of viruses to host functional constraints.

Project description:BackgroundThe bacterial flagellum is the most important organelle of motility in bacteria and plays a key role in many bacterial lifestyles, including virulence. The flagellum also provides a paradigm of how hierarchical gene regulation, intricate protein-protein interactions and controlled protein secretion can result in the assembly of a complex multi-protein structure tightly orchestrated in time and space. As if to stress its importance, plants and animals produce receptors specifically dedicated to the recognition of flagella. Aside from motility, the flagellum also moonlights as an adhesion and has been adapted by humans as a tool for peptide display. Flagellar sequence variation constitutes a marker with widespread potential uses for studies of population genetics and phylogeny of bacterial species.ResultsWe sequenced the complete flagellin gene (flaA) in 18 different species and subspecies of Aeromonas. Sequences ranged in size from 870 (A. allosaccharophila) to 921 nucleotides (A. popoffii). The multiple alignment displayed 924 sites, 66 of which presented alignment gaps. The phylogenetic tree revealed the existence of two groups of species exhibiting different FlaA flagellins (FlaA1 and FlaA2). Maximum likelihood models of codon substitution were used to analyze flaA sequences. Likelihood ratio tests suggested a low variation in selective pressure among lineages, with an omega ratio of less than 1 indicating the presence of purifying selection in almost all cases. Only one site under potential diversifying selection was identified (isoleucine in position 179). However, 17 amino acid positions were inferred as sites that are likely to be under positive selection using the branch-site model. Ancestral reconstruction revealed that these 17 amino acids were among the amino acid changes detected in the ancestral sequence.ConclusionThe models applied to our set of sequences allowed us to determine the possible evolutionary pathway followed by the flaA gene in Aeromonas, suggesting that this gene have probably been evolving independently in the two groups of Aeromonas species since the divergence of a distant common ancestor after one or several episodes of positive selection.ReviewersThis article was reviewed by Alexey Kondrashov, John Logsdon and Olivier Tenaillon (nominated by Laurence D Hurst).

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Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection.

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Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection.

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