Abstract
BackgroundHIV can evolve drug resistance rapidly in response to new drug treatments, often through a combination of multiple mutations [1-3]. It would be useful to develop automated analyses of HIV sequence polymorphism that are able to predict drug resistance mutations, and to distinguish different types of functional roles among such mutations, for example, those that directly cause drug resistance, versus those that play an accessory role. Detecting functional interactions between mutations is essential for this classification. We have adapted a well-known measure of evolutionary selection pressure (Ka/Ks) and developed a conditional Ka/Ks approach to detect important interactions.ResultsWe have applied this analysis to four independent HIV protease sequencing datasets: 50,000 clinical samples sequenced by Specialty Laboratories, Inc.; 1800 samples from patients treated with protease inhibitors; 2600 samples from untreated patients; 400 samples from untreated African patients. We have identified 428 mutation interactions in Specialty dataset with statistical significance and we were able to distinguish primary vs. accessory mutations for many well-studied examples. Amino acid interactions identified by conditional Ka/Ks matched 80 of 92 pair wise interactions found by a completely independent study of HIV protease (p-value for this match is significant: 10-70). Furthermore, Ka/Ks selection pressure results were highly reproducible among these independent datasets, both qualitatively and quantitatively, suggesting that they are detecting real drug-resistance and viral fitness mutations in the wild HIV-1 population.ConclusionConditional Ka/Ks analysis can detect mutation interactions and distinguish primary vs. accessory mutations in HIV-1. Ka/Ks analysis of treated vs. untreated patient data can distinguish drug-resistance vs. viral fitness mutations. Verification of these results would require longitudinal studies. The result provides a valuable resource for AIDS research and will be available for open access upon publication at ReviewersThis article was reviewed by Wen-Hsiung Li (nominated by Eugene V. Koonin), Robert Shafer (nominated by Eugene V. Koonin), and Shamil Sunyaev.
Highlights
HIV can evolve drug resistance rapidly in response to new drug treatments, often through a combination of multiple mutations [1,2,3]
We have extended the Ka/Ks concept to consider interactions with other sites, by formulating a conditional Ka/Ks that measures the effects of mutations at one site on the selection pressure for mutations at another site
Detection of selection pressure interactions via conditional Ka/Ks To dissect the functional roles of amino acid mutations in HIV protease, we analyzed the Specialty dataset of 48,387 HIV-positive samples for conditional Ka/Ks relationships
Summary
HIV can evolve drug resistance rapidly in response to new drug treatments, often through a combination of multiple mutations [1,2,3]. During the past two decades, researchers and clinicians have made enormous efforts to identify drug resistance mutations in HIV-1 protease, a major target of anti-retroviral therapy. Over the last 20 years, many mutations and combinations of mutations in protease have been reported to play a role in drug resistance [4,5]. This discovery process is laborious, expensive, and far from automatic – it is research. A completely automated approach for identifying drug resistance mutations would be valuable [9,10]
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