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Dynamical basis for drug resistance of HIV-1 protease.

ABSTRACT: BACKGROUND: Protease inhibitors designed to bind to protease have become major anti-AIDS drugs. Unfortunately, the emergence of viral mutations severely limits the long-term efficiency of the inhibitors. The resistance mechanism of these diversely located mutations remains unclear. RESULTS: Here I use an elastic network model to probe the connection between the global dynamics of HIV-1 protease and the structural distribution of drug-resistance mutations. The models for study are the crystal structures of unbounded and bound (with the substrate and nine FDA approved inhibitors) forms of HIV-1 protease. Coarse-grained modeling uncovers two groups that couple either with the active site or the flap. These two groups constitute a majority of the drug-resistance residues. In addition, the significance of residues is found to be correlated with their dynamical changes in binding and the results agree well with the complete mutagenesis experiment of HIV-1 protease. CONCLUSIONS: The dynamic study of HIV-1 protease elucidates the functional importance of common drug-resistance mutations and suggests a unifying mechanism for drug-resistance residues based on their dynamical properties. The results support the robustness of the elastic network model as a potential predictive tool for drug resistance.

SUBMITTER: Mao Y

PROVIDER: S-EPMC3149572 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Dynamical basis for drug resistance of HIV-1 protease.

Mao Yi Y

BMC structural biology 20110708

<h4>Background</h4>Protease inhibitors designed to bind to protease have become major anti-AIDS drugs. Unfortunately, the emergence of viral mutations severely limits the long-term efficiency of the inhibitors. The resistance mechanism of these diversely located mutations remains unclear.<h4>Results</h4>Here I use an elastic network model to probe the connection between the global dynamics of HIV-1 protease and the structural distribution of drug-resistance mutations. The models for study are th ...[more]

PMID: 21740562

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Project description:BackgroundHIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors.Methods and findingsWe have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy.ConclusionsHIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy.

Dataset Information

Dynamical basis for drug resistance of HIV-1 protease.

Publications

Dynamical basis for drug resistance of HIV-1 protease.

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