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.
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&emsp14;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.
Hu
Qinxue
Q
Centre for Infection and Immunity, St George's University of London, London, UK.
Huang
Xin
X
Shattock
Robin J
RJ
D000577:Amides / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D000077592:Maraviroc; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism*; D015728:Receptors, HIV / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D000577:Amides; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D011720:Pyrazoles; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D015728:Receptors, HIV; D014230:Triazoles; D054299:env Gene Products, Human Immunodeficiency Virus; C119369:TAK 779; D014633:Valine; D000077592:Maraviroc
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