title: Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization.
abstract: The opiates are well-established immunomodulatory factors, and recent evidence suggests that mu- and delta-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 mu- and delta-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-1alpha/CXCL12 were inhibited following opioid pretreatment. Studies were performed with primary monocytes and Chinese hamster ovary cells transfected with CCR5 and the micro-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.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140, USA. rogerst@temple.edu
authors.forename: Imre
authors.initials: I
authors.lastname: Szabo
authors.forename: Michele A
authors.initials: MA
authors.lastname: Wetzel
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Amber D
authors.initials: AD
authors.lastname: Steele
authors.forename: David E
authors.initials: DE
authors.lastname: Kaminsky
authors.forename: Chongguang
authors.initials: C
authors.lastname: Chen
authors.forename: Lee-Yuan
authors.initials: LY
authors.lastname: Liu-Chen
authors.forename: Filip
authors.initials: F
authors.lastname: Bednar
authors.forename: Earl E
authors.initials: EE
authors.lastname: Henderson
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D002633:Chemotaxis; D006224:Cricetinae; D003888:Desensitization, Immunologic; D004198:Disease Susceptibility; D016655:HIV Core Protein p24 / Q000235:genetics; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D009000:Monocytes / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000502:physiology; D015398:Signal Transduction; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016655:HIV Core Protein p24; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D002118:Calcium