Zhang Xiao-Min, Zhang Qiwei, Wu Hao, Lau Terrence Chi-Kong, Liu Xuan, Chu Hin, Zhang Ke, Zhou Jie, Chen Zhi-Wei, Jin Dong-Yan, Zheng Bo-Jian
1 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR, China .
2 Biosafety Level-3 Laboratory, School of Public Health and Tropical Medicine, Southern Medical University , Guangzhou, China .
AIDS Res Hum Retroviruses. 2016 Sep;32(9):909-17. doi: 10.1089/AID.2015.0359. Epub 2016 May 9.
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.
高效抗逆转录病毒治疗实施后，耐药突变的出现日益增多。为了表征HIV-1循环重组型08_BC（CRF08_BC）亚型逆转录酶（RT）引物结合区的两个新突变L228I和Y232H，构建了两个突变克隆以确定它们对病毒表型易感性和复制能力（RC）的影响。结果显示，新突变L228I本身对依曲韦林产生低水平耐药。L228I与Y188C组合对奈韦拉平（NVP）和依非韦伦（EFV）均表现出高水平交叉耐药。A139V和Y232H共同存在诱导对NVP和EFV产生中度耐药。与野生型（WT）参考病毒相比，突变Y188C/L228I、A139V、Y232H以及A139V/Y232H使病毒RC降低超过55%。建模研究表明，Y188C/L228I或A139V/Y232H共同存在可能诱导RT构象变化，这可能由于氢键消除或与邻近残基的复杂相互作用导致药物敏感性降低和病毒RC下降。我们的结果表明，L228I和Y232H是新的与非核苷类逆转录酶抑制剂耐药相关的辅助性突变，并为临床医生为感染HIV-1 CRF08_BC亚型的患者设计更有效的治疗方案提供了有价值的信息。
