期刊
JOURNAL OF GENERAL VIROLOGY
卷 91, 期 -, 页码 2965-2973出版社
MICROBIOLOGY SOC
DOI: 10.1099/vir.0.025270-0
关键词
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资金
- Hotung Trust NIAID [U19 AI76982]
- EC [037611]
- Ministry of Science and Technology of China [2006CB504200, 2008ZX10001 002, 2008ZX10001 015]
- NIH [AI 0678501]
- National Natural Science Foundation of China [30872357]
The envelope glycoprotein (Env) of human immunodeficiency virus is key to viral entry of susceptible target cells and is therefore a major target for the design of vaccines and antiviral drugs C-C chemokine receptor type 5 (CCR5)-using (R5) Env is the predominant phenotype associated with early transmission and acute infection This study investigated the mechanism of CCR5 use and the sensitivity to CCR5 inhibitors of a panel of transmitted or early founder (T/F) Envs The data showed that the majority of T/F Envs used CCR5 and that many also used CCR3, although less efficiently Despite a similar ability to use wild-type CCR5, individual Envs differed significantly in their sensitivity to the CCR5 inhibitors maraviroc, CMPD-167 and SCH-412147 Inhibitor mapping experiments demonstrated that maraviroc CMPD-167 and SCH-412147 interfered with the binding of CCR5 mAb to the C-terminal half of the second extracellular loop 2 of CCR5 Interestingly, Envs resistant to maraviroc, CMPD167 and SCH-412147 remained sensitive to TAK-779 Further studies indicated that the sensitivity of Envs to CCR5 inhibitors correlated with the molecular anatomy of CCR5 use, revealing that the inhibitor-sensitive Envs barely used the CCR5 N terminus, whereas resistant Envs showed a marked increase in its use Taken together, these findings demonstrate that T/F R5 Envs are heterogeneous with respect to the mechanisms of CCR5 utilization These data may have implications for therapeutic and prophylactic use of CCR5-based antiretrovirals
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