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In certain regions, up to 40% of HIV infected individuals are believed to abuse opioids (UN Joint Programme on HIV/AIDS (UNAIDS), 2013). Opioid users also suffer from a faster progression of infection to AIDS, as well as severe long term consequences such as neurocognitive defects in both humans and non-human primate models studied (Kapadia et al., 2005; Rivera-Amill et al., 2010; Byrd et al., 2011). Studies using peripherally acting ��-opioid receptor antagonist methylnaltrexone indicate that opioids can increase the infectivity of cells and viremia, which are mediated by the peripheral ��-opioid receptors (Ho et al., 2003). Most recent studies have focused on how opioid abuse promotes neurocognitive dysfunction like HIV-associated neurocognitive disorders (HAND) in the infected individuals. All these studies consistently showed that opioid abusers experience more severe neurocognitive defects including HIV-associated dementia (Bell et al., 1998, 2006). Further mechanistic studies correlate the increased neurotoxicity of HIV in opioid abusers with up-regulated inflammation (Gurwell et al., 2001; El-Hage et al., 2008; Bokhari et al., 2009). However, the effects of opioid abuse on GI homeostasis during HIV infection are not well studied although both opioids and HIV have been shown to disrupt the intestinal homeostasis through the similar pathways (Figure ?Figure55). As previously described, both HIV/SIV infection and morphine treatment can induce the intestinal epithelial barrier damage. Indeed, humans infected with HIV who use heroin have been shown to have greater amounts of LPS in their serum compared with non-users (Ancuta et al., 2008), implying that disruption of barrier function within the gut is more severe in drug using HIV patients. An investigation of gut biopsy from HIV-infected patients displays microtubule depolymerization, which is expected to be associated with intestinal tight junction disorganization and as a result of MLCK activation (Clayton et al., 2001; Turner, 2006). Interestingly, our study also shows that morphine treatment alone induces intestinal tight junction disruption and bacterial translocation by activating MLCK (Meng et al., 2013). Therefore, it is conceivable that opioids and HIV infection either synergistically or additively modulate MLCK activation explaining the more sever gut barrier dysfunction observed in drug abusing HIV infected patients. This was recently OTX015 price validated by our studies where it was demonstrated that opioids exacerbated HIV induced gut barrier disruption, increased bacterial translocation from the gut lumen, and sustained systemic inflammation with an increase in both IL-6 and TNF-�� using a rodents model of HIV (Sindberg et al., 2014). FIGURE 5 Both human immunodeficiency virus (HIV) infection and opioid abuse induce disruption of gut homeostasis.