Disruption of Gut Homeostasis by Opioids in the Early Stages of HIV Infection

Abstract

Opioids are a common comorbidity with HIV, with the use of opioids being present in up to 40% of the HIV infected population in some countries. Opioids have been shown to worsen HIV pathogenesis, including increased viral replication and faster progression to AIDS. HIV pathogenesis has been shown to be important in the gastrointestinal tract, where early loss of CD4+ T-cells has been observed in SIV infection and infection with either HIV or SIV show evidence of systemic bacterial translocation which is believed to drive HIV replication. Opioids are believed to worsen this effect and have been shown to increase bacterial translocation in HIV patients. The second chapter study was performed to understand the underlying disruption of gut homeostasis that contributes to bacterial translocation. HIV models were validated to show bacterial translocation, and then look at gut morphology, tight junction localization on gut epithelium, and immune function within the gut at early time points of exposure to HIV infection. Overall, based on the measures examined, opioids enhanced the pathogenesis of HIV in the gut at early infection which likely contributes to the greater replication and faster development of AIDS. While the loss of gut homeostasis is strongly believed to occur at least in part through changes in the host defenses in the gut, namely on immune populations and epithelial barrier integrity, recent evidence suggests that the microbiome of late stage HIV infected individuals is altered and may contribute to the observed disruption. The third chapter investigated the microbiome in early HIV infection to see if dysbiosis occurs, and whether opioids are associated with earlier changes. Using two animals models of infectious HIV, microbial dysbiosis was not observed at early time points of infection in either model. However, this study shows for the first time that morphine induced strong changes in the microbiome, which likely occurs via a combination of constipation and immune mediated effects. Altogether, these findings suggests another mechanism for morphine influencing HIV pathogenesis at early stages of disease. Combined, these studies show the wide ranging effects that opioids and HIV have on gut defenses, including epithelial barrier, immune function, and dysbiosis from the normal microbiome. While mostly descriptive in nature, the results give potential therapeutic opportunities, including potential oral administration of TLR2 and TLR4 antagonists, opioid antagonist naloxone, and bile acids in order to supplement deficiencies in metabolites observed.