Although translational, “bench-to-bedside”, research is important, reverse-translational approaches and multiple preclinical models are essential to better understand complex disease and improve established therapies (Singer 2019). Evidence suggests that HIV compartmentalizes within the CNS early during the course of the infection establishing a separate reservoir harboring “intact proviral” HIV (Churchill et al. 2016; Bruner et al. 2019) within resident neural cell populations (Bednar et al. 2015; Sturdevant et al. 2015; Veenhuis et al. 2019) and perivascular macrophages (Fischer-Smith et al. 2001; Burdo et al. 2013; Rappaport and Volsky 2015). Preclinical studies assessing opioid interactions with HIV or viral proteins permit mechanistic understanding of how particular CNS cell types, including neurons, astroglia, and microglia are affected and contribute to accentuating effects of opiates on neuroHIV, which are discussed in detail below.