Abstract
Although combination antiretroviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Most of this knowledge is derived from studies of subtype B genotypes, despite not being the most abundant subtype worldwide. Here, we present a methodology for the comparison of mutational networks in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational networks from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models for a larger number of resistance mutations and develop a statistical test to assess differences in the inferred mutational networks between two groups. We apply this method to infer the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional cohort of HIV-1 subtype C genotypes from South Africa, as well as to a data set of subtype B genotypes obtained from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. The inferred mutational networks for subtype B versus C are significantly different sharing only five constraints on the order of accumulating mutations with mutation at residue 54 as the parental event. The results also suggest that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational networks between any two groups.
Highlights
HIV-1 infections are clinically manageable by combining two or more antiretroviral drugs [1], but the accumulation of drug resistance mutations, a process driven by the evolutionary escape dynamics of HIV-1, still limits their success [2, 3]
Subtype B is predominant in America, Australia and western and central Europe, and most therapeutic strategies are based on research and clinical studies on this subtype
We present a statistical framework enabling the comparison of patterns of accumulating mutations in different HIV-1 subtypes
Summary
HIV-1 infections are clinically manageable by combining two or more antiretroviral drugs [1], but the accumulation of drug resistance mutations, a process driven by the evolutionary escape dynamics of HIV-1, still limits their success [2, 3]. These therapies, largely developed based on studies of HIV-1 subtype B viruses, have been shown to be effective in controlling infection without subtype-specific differences [4]. We investigate the rate and partial order of accumulation of drug resistance mutations in different HIV-1 subtypes. It is important to understand whether the evolution of drug resistance in subtype C proceeds in a similar fashion as for subtype B
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