The cell type specific interactions between CCR5 and MOR were noted when using a bivalent ligand derivative of maraviroc linked to an opioid antagonist, naltrexone, with HIV-1 entry being significantly blocked in astrocytes but not microglia (El-Hage et al. 2013) (Fig. 5). Interestingly, maraviroc’s antiviral effects are completely negated in both astrocytes and microglia when morphine is present suggesting that maraviroc therapy may not be effective with opiate co-exposure. Importantly, unlike maraviroc, the bivalent compound blocked HIV entry in astrocytes irrespective of morphine treatment, while exacerbating HIV infectivity in morphine co-exposed microglia and revealing fundamental differences in the regulation of MOR and CCR5 expression in these glial types. Whereas, MOR and CCR5 expression appear to be similarly regulated in astrocytes, their expression patterns in microglia appear to be inversely correlated upon HIV and/or morphine exposure, with CCR5 being expressed at much higher levels than MOR (see El-Hage et al. 2013). The differential effects of the bivalent ligand in astrocytes compared to microglia might be due to the fact that the expression levels of MOR and CCR5 are differentially regulated by HIV in each of the cell types (El-Hage et al. 2013; Yuan et al. 2013; Arnatt et al. 2016).
Fig. 5 Differential inhibition of HIV-1 entry into human glia by maraviroc and a bivalent CCR5-MOR antagonist (BVL) with cell-specific interactions in combination with morphine. (a) Construction of a MOR-CCR5 heterodimer model in a membrane (gray), and aqueous surrounds (red) system. The green protein represents MOR and the blue protein represents CCR5, while the bivalent ligand is colored in yellow. (b) Different binding pocket (green) for the triazole moiety of the bivalent ligand yellow) at 0 ns and 6.0 ns. (c) Construction of a chemical probe that interacts with both the MOR and CCR5 receptors simultaneously. To monitor HIV-1 infection (d) astrocytes and (e) microglia were transfected with a pBlue3′LTR-luc reporter sensitive to Tat expression and luciferase activity was measured. Data indicate that maraviroc’s antiviral effects are completely negated in both astrocytes and microglia when morphine is present (red bars). Interestingly, unlike maraviroc, the bivalent compound blocked HIV entry in astrocytes irrespective of morphine treatment. By contrast, the bivalent antagonist exacerbated HIV infectivity in microglia in the presence of morphine (red bars). The findings reveal fundamental differences in co-regulation of MOR and CCR5 expression in astroglia and microglia upon HIV and/or morphine exposure (see El-Hage et al. 2013). Values are luminescence intensity ± SEM from 3 to 5 independent experiments at 18 h post-infection (*p < 0.005 vs. un-infected cells; $p < 0.05 vs. R5 HIV-1; #p < 0.05 vs. R5 + morphine (M); ¶p < 0.05 vs. R5 + maraviroc (MVC); §p < 0.05 vs. R5 + M + MVC; ¥p < 0.05 vs. R5 + M + MVC + naltrexone). (a–b) Modified and reprinted with permission from Arnatt et al. (2016). (c–e) Modified and reprinted with permission from El-Hage et al. (2013)