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.

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.

• Authors: Qinxue Hu, Xin Huang, Robin J Shattock
• Journal: The Journal of general virology (J Gen Virol) Vol. 91 Issue Pt 12 Pg. 2965-73 (Dec 2010) ISSN: 1465-2099 [Electronic] England
• PMID: 20810746 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Antibodies, Monoclonal
• CCR5 Receptor Antagonists
• CMPD 167
• Cyclohexanes
• HIV Fusion Inhibitors
• Pyrazoles
• Quaternary Ammonium Compounds
• Receptors, CCR5
• Receptors, HIV
• Triazoles
• env Gene Products, Human Immunodeficiency Virus
• TAK 779
• Valine
• Maraviroc

Topics

• Amides (pharmacology)
• Antibodies, Monoclonal (metabolism)
• CCR5 Receptor Antagonists
• Cyclohexanes (pharmacology)
• HIV Fusion Inhibitors (pharmacology)
• HIV-1 (physiology)
• Humans
• Maraviroc
• Protein Binding
• Pyrazoles (pharmacology)
• Quaternary Ammonium Compounds (pharmacology)
• Receptors, CCR5 (metabolism)
• Receptors, HIV (antagonists & inhibitors, metabolism)
• Triazoles (pharmacology)
• Valine (analogs & derivatives, pharmacology)
• Virus Internalization
• env Gene Products, Human Immunodeficiency Virus (metabolism)