TY - JOUR
T1 - 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
AU - Tanuma, Junko
AU - Hachiya, Atsuko
AU - Ishigaki, Kyoko
AU - Gatanaga, Hiroyuki
AU - Minh Lien, Trinh Thi
AU - Hien, Nguyen Duc
AU - Van Kinh, Nguyen
AU - Kaku, Mitsuo
AU - Oka, Shinichi
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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.
KW - A371V
KW - CRF01_AE
KW - Drug resistance
KW - G335D
KW - Reverse transcriptase
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U2 - 10.1016/j.micinf.2010.08.003
DO - 10.1016/j.micinf.2010.08.003
M3 - Article
C2 - 20713171
AN - SCOPUS:78649898894
VL - 12
SP - 1170
EP - 1177
JO - Microbes and Infection
JF - Microbes and Infection
SN - 1286-4579
IS - 14-15
ER -