The ability of opiates to modulate HIV infection and HIV neuropathogenesis/disease progression may be partly due to the interactive effects seen between the opioid and chemokine receptors, specifically MOR and CCR5 or CXCR4 (Rogers and Peterson 2003; Steele et al. 2003; Szabo et al. 2003; Festa and Meucci 2012). The potential mechanisms for this interaction can include heterologous cross-desensitization via downstream signaling (Rogers et al. 2000; Steele et al. 2002; Song et al. 2011) and/or potentially via direct opioid-chemokine receptor dimeric or heteromeric interactions (Suzuki et al. 2002; Chen et al. 2004; Nash and Meucci 2014). MOR and DOR activation can heterologously desensitize CCR5 responsiveness to CCL3, CCL4, and CCL5 in monocytes (Grimm et al. 1998; Szabo et al. 2003; Chen et al. 2004). The cross-desensitization appears to be regulated by MOR-dependent PKCζ activation and CCR5 phosphorylation and downregulation (Song et al. 2011). Alternatively, MOR-induced downregulation of CCL2 and CCL4 mRNA reciprocally upregulates the expression of their associated receptors, CCR2b, CCR3, and CCR5 (Mahajan et al. 2005). A previous study reported significant upregulation of CCR5 and CXCR4 expression in CD14 monocytes with [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), a MOR ligand, exposure with enhanced replication of both X4- and R5-tropic viral strains of HIV (Steele et al. 2003). For CXCR4, bidirectional heterologous desensitization is less evident with MOR but has been reported for KOR, with Ca2+ signaling experiments suggesting that cross-desensitization occurs within seconds of KOR or CXCR4 activation in a concentration-dependent manner (Finley et al. 2008). Thus, opiates acting at different opioid receptors in the presence of HIV appear to activate chemokine receptor signaling and can contribute to the synergistic effects of HIV and opioid drug co-exposure seen in neuroHIV progression.