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Analysis of mutational history of multidrug‐ resistant genotypes with a mutagenetic tree model

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Resumo:Human immunodeficiency virus (HIV) can develop resistance to all antiretroviral drugs. Multidrug resistance, however, is a rare event in modern HIV treatment, but can be life‐threatening, particular in patients with very long therapy histories and in areas with limited access to novel drugs. To understand the evolution of multidrug resistance, we analyzed the EuResist database to uncover the accumulation of mutations over time. We hypothesize that the accumulation of resistance mutations is not acquired simultaneously and randomly across viral genotypes but rather tends to follow a predetermined order. The knowledge of this order might help to elucidate potential mechanisms of multidrug resistance. Our evolutionary model shows an almost monotonic increase of resistance with each acquired mutation, including less well‐known nucleoside reverse transcriptase (RT) inhibitor‐related mutations like K223Q, L228H, and Q242H. Mutations within the integrase (IN) (T97A, E138A/K G140S, Q148H, N155H) indicate high probability of multidrug resistance. Hence, these IN mutations also tend to be observed together with mutations in the protease (PR) and RT. We followed up with an analysis of the mutation‐specific error rates of our model given the data. We identified several mutations with unusual rates (PR: M41L, L33F, IN: G140S). This could imply the existence of previously unknown virus variants in the viral quasispecies. In conclusion, our bioinformatics model supports the analysis and understanding of multidrug resistance.
Autores principais:Abecasis, AB
Outros Autores:Vandamme, AM; the EuResist Network Study Group
Assunto:antiretrovirus drug antiviral agents disease control evolution human immunodeficiency virus infection mutation/mutation rate reservoir resistance virus classification QR180 Immunology QR355 Virology RA0421 Public health. Hygiene. Preventive Medicine RM Therapeutics. Pharmacology Infectious Diseases Virology Public Health, Environmental and Occupational Health Pharmacology, Toxicology and Pharmaceutics(all) SDG 3 - Good Health and Well-being SDG 17 - Partnerships for the Goals
Ano:2023
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso aberto
Instituição associada:Universidade Nova de Lisboa
Idioma:inglês
Origem:Repositório Institucional da UNL

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