Chronic Opioid use and abuse has been well documented to induce bacterial translocation and sustained immune activation. In HIV patients, accumulating clinical observations show a strong correlation between microbial translocation and HIV disease progression. Given the overall detrimental effect of sustained microbial translocation on host health, it is conceivable that therapies to prevent/block microbial translocation can be exploited as novel therapeutic intervention in HIV/AIDS and may be particularly beneficial in HIV patients that are opioid users/abusers. The gut microbiota, play a significant role in maintaining gut homeostasis and gut barrier integrity. Disruption in the composition of intestinal microbes has been shown to have important implications in the development of a number of disease processes. Loss of microorganisms which are part of the normal flora of healthy hosts increases the susceptibility to a more virulent composition of organism that can contribute to barrier disruption and microbial translocation. Thus far, very little is known regarding the role of the gu microbiota in the underlying mechanisms involved in the increased microbial translocation in either opioid abusers or in HIV patients. This lack of knowledge has important negative health- related implications since gut microbial translocation leading to immune activation contributes to AIDS related pathology and possibly HAND. Our preliminary data show for the first time that when community composition dissimilarity was analyzed using microbiota profiles morphine treatment resulted in a significantly different cluster in gut bacterial microbial composition compared to placebo animals. Furthermore, factors that contribute to microbial dysbiosis such as significant decrease in the number of bacterial community and reduced bacterial diversity was also observed in the morphine treated group. Based on our preliminary data, we hypothesize that morphine modulation of the gut microbiota and its virulence play a central role in morphine and morphine +HIV induced intestinal barrier disruption. This results in increased bacterial translocation, immune activation and contributes to HIV disease progression. To test the hypothesis we will in Aim 1: Determine the abundance and species diversity of the microbiota community (stool and mucosa associated) following morphine treatment and in the context of HIV infection and its contribution to gut barrier disruption and systemic microbial translocation and immune activation.
Aim 2 : Determine the virulence traits, clonality, and antibiotic resistance of the mucosa-associated microbial community in morphine treated animals and in the context of HIV. (Enteropathogenic Escherichia coli).
Aim 3 : Determine the therapeutic potential of methyl naltrexone and TLR2 antagonists in morphine HIV induced modulation of gut microbiota and bacterial virulence.
The latest statistics on the world epidemic of AIDS &HIV (UNAIDS/WHO, November 2005) report that at least 40 million people are infected with HIV with nearly 6 million cases of AIDS world-wide. There is a strong correlation between chronic drug use and increase susceptibility to HIV infection. Chronic drug users accounts for approximately a third of all cases of AIDS in the USA and the progression to AIDS dementia is markedly accelerated in opiate drug abusers. This proposal postulates that modulation of microbiota by opioid drug abuse and HIV1 infection may be a plausible mechanism for the persistent immune activation in these patients. Until now there are no published studies implicating microbiota in the dysregulated immune activation observed in HIV infected drug abusing population. These studies will allow for the delineation of the mechanisms and allow for the development of new therapeutic strategies to attenuate immune activation and reverse HIV disease progression both in HIV infected patients and in HIV infected drug abusing population.