@article{mbs:/content/journal/jgv/10.1099/vir.0.025270-0, author = "Hu, Qinxue and Huang, Xin and Shattock, Robin J.", title = "C-C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors", journal= "Journal of General Virology", year = "2010", volume = "91", number = "12", pages = "2965-2973", doi = "https://doi.org/10.1099/vir.0.025270-0", url = "https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.025270-0", publisher = "Microbiology Society", issn = "1465-2099", type = "Journal Article", abstract = "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.", }