Few studies have examined the interplay between opioids, neural progenitors and HIV/HIV proteins. Sustained exposure (4 d) to morphine (500 nM) and Tat1–72 (100 nM) decreased the viability of MOR-expressing striatal glial precursors, and to a lesser extent astrocytes, and this coincided with caspase-3 activation (Khurdayan et al. 2004). By contrast, comparably administered morphine or Tat alone was sufficient to decrease the viability of immature glia/glial progenitors in spinal cord cultures, while Tat and morphine failed to interact (Buch et al. 2007). Collectively, these findings were the first to indicate that opioid and/or Tat could enhance programmed cell death in subpopulations of glial precursors in a developmentally regulated and region-dependent manner (Khurdayan et al. 2004; Buch et al. 2007). In human glial progenitors, co-administering morphine (500 nM) increased the antiproliferative effects of Tat (12–48 h) or conditioned medium from HIV-1SF162-infected MDMs (12 h), while paradoxically reversing the antiproliferative effects from HIV-1IIIB conditioned medium (12 h) (Hahn et al. 2012). In these studies, Tat or HIV exposure reduced the proliferation of Sox2+ and Olig2+ undifferentiated glial and oligodendroglial progenitors, respectively, while progenitor viability was unchanged (Hahn et al. 2012). In human neural progenitor cells (hNPCs), sustained infection with R5-tropic HIVBaL increased the proliferation and premature differentiation of hNPCs into both neurons and astrocytes, and both measures were significantly enhanced by morphine co-exposure (Balinang et al. 2017). Importantly, immunoneutralizing antibodies (Hahn et al. 2012) or the selective antagonist, maraviroc (Balinang et al. 2017), were able to significantly attenuate the consequences of R5-tropic HIV infection on hNPC differentiation and fate confirming a direct role of CCR5 in these processes. Lastly, decreases in the proliferation of hNPCs seen with morphine and Tat are, in part, regulated by ERK1/2-dependent increases in p53 and p21 expression (Malik et al. 2014) and can be modulated by PDGF BB suggesting a possible therapeutic target (Malik et al. 2011). Thus, morphine can exaggerate R5-tropic HIV-induced alterations in the maturation and fate of human and rodent NPCs, thereby further disrupting the balance of neural cell types and CNS function.