Structural effects of HIV-1 subtype C integrase mutations on the activity of integrase strand transfer inhibitors in South African patients

Abstract

HIV-1 integrase enzyme is responsible for the integration of viral DNA into the host genomic DNA. Integrase strand transfer inhibitors (INSTIs) are highly potent antiretroviral agents that inhibit this process, and are internationally approved for the treatment of both naïve and treated HIV-1 patients. However, their long-term efficacy is threatened by development of drug resistance strains resulting in resistance mutations. This work aimed to examine the effect of INSTI resistance-associated mutations (RAMs) and polymorphisms on the structure of HIV-1 subtype C (HIV-1C) integrase. Genetic analysis was performed on seven HIV-1C infected individuals with virologic failure after at least 6 months of INSTI-based antiretroviral therapy, presenting at the King Edward VIII hospital in Durban, South Africa. These were compared with sequences from 41 INSTI-naïve isolates. Integrase structures of selected isolates were modeled on the SWISS model online server. Molecular docking and dynamics simulations were also conducted using AutoDock-Vina and AMBER 18 force fields, respectively. Only one INSTI-treated isolate (14.28%) harboured major mutations (G140A + Q148R) as well as the E157Q minor mutation. Interestingly, S119T and V151I were only found in patients failing raltegravir (an INSTI drug). Molecular modeling and docking showed that RAMs and polymorphisms associated with INSTI-based therapy affect protein stability and this is supported by their weakened hydrogen-bond interactions compared to the wild-type. To the best of our knowledge, this is the first study to identify a double mutant in the 140’s loop region from South African HIV-1C isolates and study its effects on Raltegravir, Elvitegravir, and Dolutegravir binding. Communicated by Ramaswamy H. Sarma