HIV, HIV-1 viral proteins, and opiate-induced barrier dysfunction is associated with increased infiltration of monocyte-derived macrophages (MDMs) into the brain. Enhanced influx of peripheral (infected) macrophages into the brain can serve to replenish viral reservoirs and further promote neuroinflammation. Several studies have examined the individual impact of HIV, Tat, or morphine on monocyte adhesion or migration into the CNS (Nottet et al. 1996; Wu et al. 2000; Fischer-Smith et al. 2001; Pello et al. 2006; Williams et al. 2013a, 2014; Strazza et al. 2016; Leibrand et al. 2017; Chilunda et al. 2019). However, fewer studies have examined the combined effects of HIV/Tat and opiates. Co-exposure of HIV-1 Tat and morphine on astrocytes increases the production of chemoattractants, primarily CCL2 and CCL5, and increases microglial migration. These effects were inhibited by MOR blockade (El-Hage et al. 2006b). Co-exposure of Tat and morphine or buprenorphine to a BBB model increases monocyte transmigration in response to CCL5 and other chemokines (Mahajan et al. 2008; Jaureguiberry-Bravo et. al. 2016). In S. pneumoniae-infected mice, morphine and/or Tat exposure significantly enhances immune cell trafficking into the brain via actions at TLR2 and TLR4 (Dutta and Roy 2015).