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.

Suppression of CCL2/MCP-1 and CCL5/RANTES expression by nociceptin in human monocytes.

The receptor designated Opioid Receptor-Like 1 (ORL1) is abundantly expressed in the central nervous system (CNS) as well as by cells of the immune system. While much is known about the function of ORL1 in the CNS, there is little information in the literature about the role of ORL1 in the immune response. There have been numerous reports documenting the effects of GPCR activation on the expression of chemokines crucial in mediating inflammatory events in biological systems. The aim of the present work was to examine the effect of nociceptin administration on the pro-inflammatory chemokine expression of human monocytes. We report here that human CD14(+) monocytes expresses the mRNA for ORL1. Our results also demonstrate that nociceptin can suppress the production of CCL2/MCP-1 and CCL5/RANTES chemokine protein in both primary CD14(+) human monocytes and monocyte-like cell lines. However, nociceptin does not appear to regulate the expression of these chemokines at the level of transcription, as CCL2/MCP-1 and CCL5/RANTES mRNA levels following nociceptin treatment of monocytes were essentially normal. Although the mechanism of chemokine regulation by nociceptin is as yet unknown, it is evident that the ORL1/nociceptin system plays a role in regulating chemotactic responses of leukocytes through chemokine suppression. Finally, these data may provide the initial basis for the development of ORL1 agonists and antagonists for therapeutic treatment of inflammatory disease.