Synthetic lethals in HIV: ways to avoid drug resistance

Abstract

BackgroundRNA viruses rapidly accumulate genetic variation, which can give rise to synthetic lethal (SL) and deleterious (SD) mutations. Synthetic lethal mutations (non-lethal when alone but lethal when combined in one genome) have been studied to develop cancer therapies. This principle can also be used against fast-evolving RNA-viruses. Indeed, targeting protein sites involved in SD + SL interactions with a drug would render any mutation of such sites, lethal.ResultsHere, we set up a strategy to detect intragenic pairs of SL and SD at the surface of the protein to predict less escapable drug target sites. For this, we detected SD + SL, studying HIV protease (PR) and reverse transcriptase (RT) sequence alignments from two groups of VIH+ individuals: treated with drugs (T) or not (NT). Using a series of statistical approaches, we were able to propose bona fide SD + SL couples. When focusing on spatially close co-variant SD + SL couples at the surface of the protein, we found 5 SD + SL groups (2 in the protease and 3 in the reverse transcriptase), which could be good candidates to form pockets to accommodate potential drugs.ConclusionsThus, designing drugs targeting these specific SD + SL groups would not allow the virus to mutate any residue involved in such groups without losing an essential function. Moreover, we also show that the selection pressure induced by the treatment leads to the appearance of new mutations, which change the mutational landscape of the protein. This drives the existence of differential SD + SL couples between the drug-treated and non-treated groups. Thus, new anti-viral drugs should be designed differently to target such groups.ReviewersThis article was reviewed by Neil Greenspan Csaba Pal and István Simon.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-015-0044-y) contains supplementary material, which is available to authorized users.

A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups

“…For this, we chose to follow a remodeled version of the seven step protocol previously described by Petitjean et al [11]. Indeed the initial procedure depicted four tests performed in parallel, three statistical nonparametric evaluations (Fisher, D ’ and r 2 ), and the semiparametric χ 2 test.…”

“…On the other hand, an SL pair is defined by two mutations which, when they appear separately have the wild-type phenotype and when they appear together, actually change this phenotype. Using the coefficient of dissimilarity ξ described by Petitjean et al [11], each interdependent pair previously determined is differentiated into CM or SL. If one considers a pair of residues A at pos i and B at pos j (A and B can be any AA), in which the number of residue pairs theoretically calculated is higher than the number of couples observed, then this coefficient is negative and corresponds to a pair of SL.…”

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