Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

Abstract

Objective: The genetic barrier for the evolution of integrase inhibitors (INIs) including raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) resistance was compared between HIV-1 subtypes CRF01_AE and B. Methods: Analysis of 66 substitutions associated with INI resistance at 41 amino acid positions in 144 nucleotide sequences (109 HIV-1 subtype CRF01_AE and 35 HIV-1 subtype B) of integrase-coding region of polymerase gene derived from INI-naive patients. Results: 28/41 studied amino acid positions were conserved, leading to a similar genetic barrier between the two subtypes. At six codon positions with different genetic barriers, six mutations (V72I, L101I, A124T, T125K, and G140C/S) displayed a higher genetic barrier and one mutation (V201I) showed a lower genetic barrier in subtype CRF01_AE than subtype B. Conclusions: Most studied amino acid positions including all corresponding to RAL and EVG primary mutations show a high level of conservation, indicating the same genetic barrier between subtypes CRF01_AE and B. Nevertheless, different genetic barriers were observed in two mutations described to be associated with DTG resistance (L101I, A124T) and other five RAL and EVG secondary mutations (V72I, T125K, G140C/S, V201I), which could have an impact on the development of resistance to RAL, EVG, and DTG.