Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization.
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.
Szabo
Imre
I
Department of Microbiology and Immunology, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140, USA. rogerst@temple.edu
Wetzel
Michele A
MA
Zhang
Ning
N
Steele
Amber D
AD
Kaminsky
David E
DE
Chen
Chongguang
C
Liu-Chen
Lee-Yuan
LY
Bednar
Filip
F
Henderson
Earl E
EE
Howard
O M Zack
OM
Oppenheim
Joost J
JJ
Rogers
Thomas J
TJ
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*
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