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EVIDENCE FOR DISRUPTION OF MG2C PAIR AS A RESISTANCE MECHANISM AGAINST HIV-1 INTEGRASE STRAND TRANSFER INHIBITORS
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Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Abstract
HIV-1 integrase is the enzyme responsible for integrating the viral DNA into the host
genome and is one of the main targets for antiretroviral therapy; however, there are
documented cases of resistance against all the currently used integrase strand transfer
inhibitors (INSTIs). While some resistance-related mutations occur near the inhibitor’s
binding site, the mutation N155H occurs on the opposite side of the drug-interacting
Mg2C ions, thus, not interacting directly with the drug molecules and currently lacking
an explanation for its resistance mechanism. Moreover, mutation N155H and the
resistance-related mutation Q148H are mutually exclusive for unknown reasons. In the
present study, we use molecular dynamics simulations to understand the impact of
the N155H mutation in the HIV-1 integrase structure and dynamics, when alone or in
combination with Q148H. Our findings suggest that the Mg2C ions of the active site
adopt different orientations in each of the mutants, causing the catalytic triad residues
involved in the ion coordination to adapt their side-chain configurations, completely
changing the INSTIs binding site. The change in the ion coordination also seems to affect
the flexibility of the terminal viral DNA nucleotide near the active site, potentially impairing
the induced-fit mechanism of the drugs. The explanations obtained from our simulations
corroborate previous hypotheses drawn from crystallographic studies. The proposed
resistance mechanism can also explain the resistance caused by other mutations that
take place in the same region of the integrase and help uncover the structural details of
other HIV-1 resistance mechanisms.
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