title: Novel Mutations L228I and Y232H Cause Nonnucleoside Reverse Transcriptase Inhibitor Resistance in Combinational Pattern.
abstract: The emergence of drug resistance mutations is increasing after the implementation of highly active antiretroviral therapy. To characterize two novel mutations L228I and Y232H in the primer grip of reverse transcriptase (RT) of HIV-1 circulating recombination form 08_BC (CRF08_BC) subtype, both mutant clones were constructed to determine their impacts on viral phenotypic susceptibility and replication capacity (RC). Results showed that the novel mutation, L228I, conferred a low-level resistance to etravirine by itself. L228I in combination with Y188C displayed a high level of cross-resistance to both nevirapine (NVP) and efavirenz (EFV). The copresence of A139V and Y232H induced a moderate level of resistance to NVP and EFV. Mutations Y188C/L228I, A139V, Y232H, and A139V/Y232H reduced more than 55% of viral RC compared with that of the wild-type (WT) reference virus. Modeling study suggested that the copresence of Y188C/L228I or A139V/Y232H might induce conformational changes to RT, which might result in reduced drug susceptibility and viral RC due to abolished hydrogen bonding or complex interaction with vicinal residues. Our results demonstrated that L228I and Y232H were novel accessory nonnucleoside reverse transcriptase inhibitor resistance-related mutations and provided valuable information for clinicians to design more effective treatment to patients infected with HIV-1 subtype CRF08_BC.
authors.affiliation: 1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: 2 Biosafety Level-3 Laboratory, School of Public Health and Tropical Medicine, Southern Medical University , Guangzhou, China .
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .|3 Guangzhou Center for Disease Control and Prevention , Guangzhou, China .
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: 4 Department of Biomedical Sciences, City University of Hong Kong , Hong Kong SAR, China .
authors.forename: Terrence Chi-Kong
authors.initials: TC
authors.lastname: Lau
authors.affiliation: 4 Department of Biomedical Sciences, City University of Hong Kong , Hong Kong SAR, China .
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: 1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: 1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: 1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Chen
authors.affiliation: 5 Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
authors.affiliation: 1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D050505:Mutant Proteins; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase