People infected with HIV (PWH) with OUD have an increased incidence of neuroHIV and CNS complications (Bell et al. 1998; Nath et al. 1999, 2000a, 2002; Anthony et al. 2008; Meyer et al. 2013; Smith et al. 2014). Injection drug use increases the probability of contracting HIV (Nath et al. 1999) and opioid drugs intrinsically alter the pathogenesis of HIV. PWH who develop intractable pain syndromes related to peripheral neuropathies often receive opioid drugs for treatment (Mirsattari et al. 1999; Denis et al. 2019). PWH who misuse opioids are more likely to undertake risky sexual behavior and are less likely to adhere to combined antiretroviral (ARV) therapy (cART) regimens (Lemons et al. 2019). Opioid receptors are widely expressed on immune cells and opioids can modulate immune function (Donahoe and Falek 1988; Plotnikoff 1988; Rouveix 1992; Adler et al. 1993; Carr and Serou 1995; Carr et al. 1996; Sheng et al. 1997; Banerjee et al. 2011; Purohit et al. 2012), which typically (but not always) result in immune suppression (Wybran et al. 1979; McDonough et al. 1980, 1981; Donahoe and Falek 1988; Donahoe et al. 1991; Falek et al. 1991; Novick et al. 1991; Chao et al. 1996a; Peterson et al. 1998; Rogers and Peterson 2003; Stein et al. 2003; Roy et al. 2006; Rittner et al. 2008). The “opiate cofactor hypothesis” proposes opioids contribute directly to the pathogenesis of acquired immune deficiency syndrome (AIDS) (Donahoe and Vlahov 1998), in part, because MOR activation can increase HIV replication in immune cells (Peterson et al. 1990, 1992, 1993, 1999; Ho et al. 2003). Furthermore, MOR and HIV co-receptors, including both CCR5 (El-Hage et al. 2013; Yuan et al. 2013; Arnatt et al. 2016) and CXCR4 (Pitcher et al. 2014) can interact via convergent downstream signaling and perhaps via direct molecular interactions (Rogers et al. 2000; Rogers and Peterson 2003; Steele et al. 2003; Chen et al. 2004; Song et al. 2011; Arnatt et al. 2016). MOR-CCR5 or CXCR4 interactions are highly contextual and can promote (Guo et al. 2002; Steele et al. 2003) or inhibit (Strazza et al. 2014) HIV expression, depending on the nature and duration of exposure (see Fig. 9; Berman et al. 2006) and cell type involved (Kim et al. 2018). Depending on the outcome measure, Tat expression reduces morphine’s efficacy and potency (Fitting et al. 2012, 2016; Hahn et al. 2016). Antagonizing CCR5 with maraviroc reinstates morphine potency in an antinociceptive assay and restores physical dependence in Tat exposed, morphine-tolerant mice (Gonek et al. 2018).