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.

Ligand stabilization of CXCR4/δ‐opioid receptor heterodimers reveals a mechanism for immune response regulation

“…The opioid effect on chemokinemediated lymphocyte migration is better established; opioids incubated with leukocytes prevent cell movement toward chemokines [12]. These observations suggest interaction; in fact, cross-desensitization processes are described between the two receptor types [8,10].Here, we observed that the combination of DOR and CXCR4 ligands specifically abolished CXCR4-induced migration and adhesion of cell lines and of primary monocytes, and that the DOR antagonist naltrindole reversed this effect. These experiments also confirmed that DPDPE promotes potent MM-1 cell adhesion, which was greater than that promoted by CXCL12, and was blocked by simultaneous CXCL12 addition.…”

“…Chemokine receptors promote immune cell migration to and adhesion at the inflammation site, whereas opioid receptors reduce pain sensation on proximal nerve endings. Opioid receptors can also regulate the immune response, as they alter antibody responses, cell-mediated immunity, phagocytic activity, adhesion and chemotaxis [8][9][10][11]. Opioids also prevent leukocyte movement toward chemokine gradients [12], and cross-desensitization is described between opioid and chemokine receptors [8,10].…”

“…Opioids also prevent leukocyte movement toward chemokine gradients [12], and cross-desensitization is described between opioid and chemokine receptors [8,10]. The CCR5 chemokine receptor can form heterodimers with each of the three opioid receptor subtypes (l, d, and j) [8,10].CXCR4, the most widely expressed chemokine receptor [13], is crucial for correct lymphocyte trafficking [14], hematopoiesis, and development [15][16][17]. It is also a coreceptor for T-tropic HIV strains [18,19], and participates in tumor cell metastasis [20][21].…”

“…The results confirmed that DOR-CXCR4 complexes also form in primary cells in a ligand-independent manner. Many reports show that CXCR4 and DOR form homoand heterodimers [8,10,22,37,38]. To determine whether these conformations are fixed or in dynamic equilibrium, we cotransfected HEK293 cells with CXCR4-CFP, CXCR4-YFP and increasing amounts of DOR.…”

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

“…CCR5 is upregulated in glia with HIV or SIV infection (Petito et al, 2001;Croitoru-Lamoury et al, 2003), suggesting Tat might increase CCL5-CCR5 signaling. By contrast, in monocytes or Chinese hamster ovary (CHO) cells, MOR or δ-opioid receptor activation causes heterologous desensitization of CCR5 and decreases infectivity by R5 HIV-1 strains (Szabo et al, 2003), suggesting that opiates attenuate CCL5-CCR5 signaling.…”