Distinct resistance patterns to etravirine and rilpivirine in viruses containing nonnucleoside reverse transcriptase inhibitor mutations at baseline

摘要

Objective: The current in-vitro study examined HIV-1 drug resistance patterns following etravirine (ETR) and rilpivirine (RPV) drug pressure in viruses containing baseline nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations. Design and method: Several baseline mutations were introduced into NL-4.3 (subtype B clone) by site-directed mutagenesis. This virus, together with two subtype C clinical isolates containing baseline mutations, was passaged in increasing drug pressure of NNRTIs in cord blood mononuclear cells. Genotypic analysis was performed at different weeks. Phenotypic resistance for ETR, RPV, and efavirenz (EFV) and the replication capacity of several mutations and combinations were tested. Results: In wild-type viruses and viruses containing K103N alone at baseline, E138K or E138G mutations were observed following pressure with either ETR or RPV prior to the appearance of other NNRTI resistance mutations. These changes were observed regardless of viral subtype. However, subtype B viruses containing Y181C generated V179I/F or A62V/A but not E138K following exposure to ETR or RPV, respectively, whereas subtype C viruses containing Y181C developed E138V together with Y188H and V179I under ETR pressure. The addition of mutations at position 138 to Y181C did not significantly enhance levels of resistance to ETR or RPV. The replicative capacity of viruses containing Y181C and either E138K or E138A was similar to that of viruses containing either E138K or E138A alone. Conclusion: These results demonstrate that ETR and RPV are likely to select for E138K as a major resistance mutation if no or very few other resistance mutations are present and that Y181C may be antagonistic to E138K.