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

Journal of Leukocyte Biology

Thomas J. Rogers⁴  Joost J. Oppenheim¹  Ning Zhang¹  David E. Kaminsky³  Filip Bednar³  Amber D. Steele³  Imre Szabo³  Lee-Yuan Liu-Chen²  Earl E. Henderson⁴  Chongguang Chen²  O. M. Zack Howard¹  Michele A. Wetzel³ 

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

关键词: chemokines;    neuroimmunology;    cell trafficking;    AIDS;   

DOI  :  10.1189/jlb.0203067

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

The opiates are well-established immunomodulatory factors, and recent evidence suggests that μ- and δ-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 δ-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-1α/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.

【 授权许可】

Unknown