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Journal of Virology, September 1998, p. 7450-7458, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Influence of the CCR2-V64I Polymorphism on Human Immunodeficiency Virus Type 1 Coreceptor Activity and on Chemokine Receptor Function of CCR2b, CCR3, CCR5, and CXCR4

Benhur Lee,1 Benjamin J. Doranz,1 Shalini Rana,2 Yanji Yi,2 Mario Mellado,3 Jose M. R. Frade,3 Carlos Martinez-A.,3 Stephen J. O'Brien,4 Michael Dean,4 Ronald G. Collman,2 and Robert W. Doms1,*

Department of Pathology and Laboratory Medicine1 and Pulmonary and Critical Care Division,2 University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Immunology and Oncology, Universidad Autónoma de Madrid, E-28049 Madrid, Spain3; and Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland 21702-12014

Received 31 March 1998/Accepted 5 June 1998

The chemokine receptors CCR5 and CXCR4 are used by human immunodeficiency virus type 1 (HIV-1) in conjunction with CD4 to infect cells. In addition, some virus strains can use alternative chemokine receptors, including CCR2b and CCR3, for infection. A polymorphism in CCR2 (CCR2-V64I) is associated with a 2- to 4-year delay in the progression to AIDS. To investigate the mechanism of this protective effect, we studied the expression of CCR2b and CCR2b-V64I, their chemokine and HIV-1 coreceptor activities, and their effects on the expression and receptor activities of the major HIV-1 coreceptors. CCR2b and CCR2b-V64I were expressed at similar levels, and neither molecule affected the expression or coreceptor activity of CCR3, CCR5, or CXCR4 in cotransfected cell lines. Peripheral blood mononuclear cells (PBMCs) from CCR2-V64I heterozygotes had normal levels of CCR2b and CCR5 but slightly reduced levels of CXCR4. CCR2b and CCR2b-V64I functioned equally well as HIV-1 coreceptors, and CCR2-V64I PBMCs were permissive for HIV-1 infection regardless of viral tropism. The MCP-1-induced calcium mobilization mediated by CCR2b signaling was unaffected by the polymorphism, but MCP-1 signaling mediated by either CCR2b- or CCR2-V64I-encoded receptors resulted in heterologous desensitization (i.e., limiting the signal response of other receptors) of both CCR5 and CXCR4. The heterologous desensitization of CCR5 and CXCR4 signaling by both CCR2 allele receptor types provides a mechanistic link that might help explain the in vivo effects of CCR2 gene variants on progression to AIDS as well as the reported antiviral activity of natural CCR2 ligands.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Pennsylvania, 806 Abramson, 34th and Civic Center Blvd., Philadelphia, PA 19104. Phone: (215) 898-0890. Fax: (215) 573-2883. E-mail: doms{at}mail.med.upenn.edu.

Journal of Virology, September 1998, p. 7450-7458, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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