Impact of CRF01_AE-specific polymorphic mutations G335D and A371V in the connection subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on susceptibility to nucleoside RT inhibitors

Certain mutations in the connection subdomain and RNase H domain of reverse transcriptase (RT) of subtype B HIV-1 contribute to resistance to nucleoside reverse transcriptase inhibitors (NRTIs). However, the impact of non-B subtype polymorphisms in this region on drug resistance remains unclear. In this study, we determined the frequencies of drug resistance mutations of the entire RT in patients with treatment failure from a cohort of Circulating recombinant form (CRF) 01_AE HIV-1-infected patients in Hanoi, Viet Nam. Subsequently, we assessed the impact of CRF01_AE polymorphisms G335D and A371V with or without thymidine analogue mutations (TAMs) on susceptibility to NRTI with recombinant viruses. In 49 patients with treatment failure, resistance mutations to NRTIs in the N-terminal half of RT were observed in 89.8%. In the C-terminal half, G335D (100%), N348I (36.8%), A371V (100%), A376S (5.3%) and A400T (97.4%) were detected, although G335D, A371V and A400T were considered polymorphisms of CRF01_AE. Drug susceptibility showed G335D, A371V, or both did not confer resistance by themselves but conferred significant resistance to NRTIs with TAMs, especially in mutants containing G335D, A371V and TAM type 2. Our results suggest the important role of CRF01_AE polymorphisms in the C-terminal half of RT in drug resistance.