Co-lethality studied as an asset against viral drug escape: the HIV protease case

Abstract

BackgroundCo-lethality, or synthetic lethality is the documented genetic situation where two, separately non-lethal mutations, become lethal when combined in one genome. Each mutation is called a "synthetic lethal" (SL) or a co-lethal. Like invariant positions, SL sets (SL linked couples) are choice targets for drug design against fast-escaping RNA viruses: mutational viral escape by loss of affinity to the drug may induce (synthetic) lethality.ResultsFrom an amino acid sequence alignment of the HIV protease, we detected the potential SL couples, potential SL sets, and invariant positions. From the 3D structure of the same protein we focused on the ones that were close to each other and accessible on the protein surface, to possibly bind putative drugs. We aligned 24,155 HIV protease amino acid sequences and identified 290 potential SL couples and 25 invariant positions. After applying the distance and accessibility filter, three candidate drug design targets of respectively 7 (under the flap), 4 (in the cantilever) and 5 (in the fulcrum) amino acid positions were found.ConclusionsThese three replication-critical targets, located outside of the active site, are key to our anti-escape strategy. Indeed, biological evidence shows that 2/3 of those target positions perform essential biological functions. Their mutational variations to escape antiviral medication could be lethal, thus limiting the apparition of drug-resistant strains.ReviewersThis article was reviewed by Arcady Mushegian, Shamil Sunyaev and Claus Wilke.

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

“…The alignments contain sequencing errors, whose percentage must be defined. In a previous article we defined this number by calculating the mutation rate of the positions necessary for the proper functioning of an active site (HIV protease [10]). This percentage was 0.3% and corresponded to that described in the literature.…”

“…However, invariant positions alone cannot constitute binding sites for a drug because of their very small number. To find the best binding sites, we applied a workflow which consists in also looking for synthetic lethals (SLs) to find durable therapeutic targets accessible to a drug [10,11]. SLs represent mutations that are not lethal but when combined make the virus unviable.…”

Relation between flexibility and positively selected HIV‐1 protease mutants against inhibitors

“…These variants, compensatory mutations, usually located far from the active site, are able to affect the enzymatic activity via molecular mechanisms that have been related to differences in the conformational flexibility,16 though these mutations have some limits. The colethality, is the documented genetic situation where two, separately nonlethal mutations, become lethal when combined in one genome, limiting the apparition of drug‐resistant strains 17…”

“…The colethality, is the documented genetic situation where two, separately nonlethal mutations, become lethal when combined in one genome, limiting the apparition of drug-resistant strains. 17 The broad use of inhibitors has selected those mutations and there are several studies that indicate mutations under positive selection. Several authors have studied the HIV-1 protease mutants from different viewpoints.…”

Synthetic lethals in HIV: ways to avoid drug resistance

“…In a preliminary work taking the HIV protease as a model, [7,21,22], we described positions involved in SDL couples. The method used yielded results comparable to those obtained by other teams working on the same subject [23][24][25].…”