Dataset Information

Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance.

ABSTRACT:

Objectives

To determine whether pan-protease inhibitor (PI)-resistant virus populations are composed predominantly of viruses with resistance to all PIs or of diverse virus populations with resistance to different subsets of PIs.

Methods

We performed deep sequencing of plasma virus samples from nine patients with high-level genotypic and/or phenotypic resistance to all licensed PIs. The nine virus samples had a median of 12 PI resistance mutations by direct PCR Sanger sequencing.

Results

For each of the nine virus samples, deep sequencing showed that each of the individual viruses within a sample contained nearly all of the mutations detected by Sanger sequencing. Indeed, a median of 94.9% of deep sequence reads had each of the PI resistance mutations present as a single chromatographic peak in the Sanger sequence. A median of 5.0% of reads had all but one of the Sanger mutations that were not part of an electrophoretic mixture.

Conclusions

The collinearity of PI resistance mutations in the nine virus samples demonstrated that pan-PI-resistant viruses are able to replicate in vivo despite their highly mutated protease enzymes. We hypothesize that the marked collinearity of PI resistance mutations in pan-PI-resistant virus populations results from the unique requirements for multi-PI resistance and the extensive cross-resistance conferred by many of the accessory PI resistance mutations.

SUBMITTER: Babrzadeh F

PROVIDER: S-EPMC3543120 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Publications

Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance.

Babrzadeh Farbod F Varghese Vici V Pacold Mary M Liu Tommy F TF Nyrén Pål P Schiffer Celia C Fessel W Jeffrey WJ Shafer Robert W RW

The Journal of antimicrobial chemotherapy 20121019 2

<h4>Objectives</h4>To determine whether pan-protease inhibitor (PI)-resistant virus populations are composed predominantly of viruses with resistance to all PIs or of diverse virus populations with resistance to different subsets of PIs.<h4>Methods</h4>We performed deep sequencing of plasma virus samples from nine patients with high-level genotypic and/or phenotypic resistance to all licensed PIs. The nine virus samples had a median of 12 PI resistance mutations by direct PCR Sanger sequencing.< ...[more]

PMID: 23085775

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Project description:BackgroundStrategies to control HIV for improving the quality of patient lives have been aided by the Highly Active Anti-Retroviral Therapy (HAART), which consists of a cocktail of inhibitors targeting key viral enzymes. Numerous new drugs have been developed over the past few decades but viral resistances to these drugs in the targeted viral enzymes are increasingly reported. Nonetheless the acquired mutations often reduce viral fitness and infectivity. Viral compensatory secondary-line mutations mitigate this loss of fitness, equipping the virus with a broad spectrum of resistance against these drugs. While structural understanding of the viral protease and its drug resistance mutations have been well established, the interconnectivity and development of structural cross-resistance remain unclear. This paper reports the structural analyses of recent clinical mutations on the drug cross-resistance effects from various protease and protease inhibitors (PIs) complexes.MethodsUsing the 2015 updated clinical HIV protease mutations, we constructed a structure-based correlation network and a minimum-spanning tree (MST) based on the following features: (i) topology of the PI-binding pocket, (ii) allosteric effects of the mutations, and (iii) protease structural stability.Results and conclusionAnalyis of the network and the MST of dominant mutations conferring resistance to the seven PIs (Atazanavir-ATV, Darunavir-DRV, Indinavir-IDV, Lopinavir-LPV, Nelfinavir-NFV, Saquinavir-SQV, and Tipranavir-TPV) showed that cross-resistance can develop easily across NFV, SQV, LPV, IDV, and DRV, but not for ATV or TPV. Through estimation of the changes in vibrational entropies caused by each reported mutation, some secondary mutations were found to destabilize protease structure. Our findings provide an insight into the mechanism of PI cross-resistance and may also be useful in guiding the selection of PI in clinical treatment to delay the onset of cross drug resistance.

Dataset Information

Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance.

Objectives

Methods

Results

Conclusions

Publications

Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance.

Similar Datasets

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