Published online before print September 12, 2003

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(Journal of Leukocyte Biology. 2003;74:1074-1082.)
© 2003 by Society for Leukocyte Biology

Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization

Imre Szabo^*,, Michele A. Wetzel^*,, Ning Zhang, Amber D. Steele^*,, David E. Kaminsky^*,, Chongguang Chen^,, Lee-Yuan Liu-Chen^,, Filip Bednar^*,, Earl E. Henderson^*,,¶, O. M. Zack Howard, Joost J. Oppenheim and Thomas J. Rogers^*,,¶

Departments of
^* Microbiology and Immunology and
Pharmacology,
Center for Substance Abuse Research, and the
^¶ Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania; and
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland

¹ Correspondence: Department of Microbiology and Immunology, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140. E-mail address: rogerst{at}temple.edu

The opiates are well-established immunomodulatory factors, and recent evidence suggests that µ- and -opioid receptor ligands alter chemokine-driven chemotactic responses through the process of heterologous desensitization. In the present report, we sought to examine the capacity of µ- and -opioids to modulate the function of chemokine receptors CCR5 and CXCR4, the two major human immunodeficiency virus (HIV) coreceptors. We found that the chemotactic responses to the CCR1/5 ligand CCL5/regulated on activation, normal T expressed and secreted, but not the CXCR4 ligand stromal cell-derived factor-1/CXCL12 were inhibited following opioid pretreatment. Studies were performed with primary monocytes and Chinese hamster ovary cells transfected with CCR5 and the µ-opioid receptor to determine whether cross-desensitization of CCR5 was a result of receptor internalization. Using radiolabeled-binding analysis, flow cytometry, and confocal microscopy, we found that the heterologous desensitization of CCR5 was not associated with a significant degree of receptor internalization. Despite this, we found that the cross-desensitization of CCR5 by opioids was associated with a decrease in susceptibility to R5 but not X4 strains of HIV-1. Our findings are consistent with the notion that impairment of the normal signaling activity of CCR5 inhibits HIV-1 coreceptor function. These results have significant implications for our understanding of the effect of opioids on the regulation of leukocyte trafficking in inflammatory disease states and the process of coreceptor-dependent HIV-1 infection. The interference with HIV-1 uptake by heterologous desensitization of CCR5 suggests that HIV-1 interaction with this receptor is not passive but involves a signal transduction process.

Key Words: chemokines • neuroimmunology • cell trafficking • AIDS

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