Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C

• Published in: PLoS computational biology Vol. 17; no. 9; p. e1008363
• Main Authors: Posada-Céspedes, Susana, Van Zyl, Gert, Montazeri, Hesam, Kuipers, Jack, Rhee, Soo-Yon, Kouyos, Roger, Günthard, Huldrych F., Beerenwinkel, Niko
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2021; Public Library of Science (PLoS)
• Subjects: Algorithms; Antiretroviral agents; Antiretroviral drugs; Bayes Theorem; Bayesian analysis; Biology and Life Sciences; Cohort Studies; Cross sections; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Viral - genetics; Gene mutations; Genetic aspects; Genotype & phenotype; Genotypes; Health aspects; HIV; HIV Infections - virology; HIV Protease Inhibitors - pharmacology; HIV-1 - classification; HIV-1 - drug effects; Human immunodeficiency virus; Humans; Infections; Lopinavir; Lopinavir - pharmacology; Mathematical models; Medicine and Health Sciences; Methods; Mutation; Networks; Parameter estimation; Physical Sciences; Probabilistic models; Protease; Protease inhibitors; Proteinase inhibitors; Random variables; Research and Analysis Methods; Residues; Statistical analysis; Statistical methods; Statistical tests; Statistics; Switzerland
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1008363

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.