Translocation of gut microbes following CD4+ T cell depletion in acute HIV infection has been implicated as a potential mechanism for immune activation in chronic HIV-1 infection and a hallmark for HIV disease progression. Interestingly, HIV patients that use intravenous heroin have higher bacterial loads when compared to non-drug using HIV infected patients. However, the mechanism underlying this defect has not been well studied. We show in preliminary data, in a murine model of drug abuse, significant increase in gut bacterial translocation in morphine treated animals when compared to placebo treated animals, which is further exacerbated in the TATtg mice treated with morphine. Strategic localization and expression of Toll-like- receptors (TLRs), on intestinal epithelial cells prevents excessive activation by gut commensal bacterial and promotes secretion of antimicrobial peptides into the gut lumen. However, dysregulated TLR activation results in barrier dysfunction, sustained bacterial translocation and chronic systemic immune activation. We show in preliminary data that morphine treatment results in a significant increase in both TLR2 and TLR4 mRNA and protein levels in gut epithelial cells and morphine induced increase in bacterial translocation is significantly attenuated in TLR2KO and TLR2/4 double knockout mice. Based on our preliminary results we hypothesize that morphine modulation of TLR expression and distribution on intestinal epithelial cells (IEL) results in tight junction proteins disruption leaing to increased bacterial translocation. Based on our preliminary data, we hypothesize, that morphine induced activation of TLRs on IEC contributes to gut barrier disruption leading to increased bacterial translocation. We further hypothesize that HIV-protein TAT will further exacerbate the pathological state.
In Aim 1 : We will determine that morphine treatment and morphine treatment in the context of HIV-1 TAT results in dysregulated TLR2 and 4 expression, aberrant TLR2 and 4 localization and persistent activation contributing to barrier disruption and gut bacterial translocation.
Aim 2 : We will determine the mechanisms how TLR expression and activation by morphine and morphine in the context of HIV 1 TAT disrupts tight junction protein organization and function.
In Aim 3 : we will determine the therapeutic potential of methylnaltrexone in the presence of Chloroquine in mitigating morphine and HIV-1 TAT modulation of gut barrier function. The results from these studies will 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.
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 TLRs on gut epithelial cells by opioid drug abuse and HIV1- TAT may be a plausible mechanism for the persistent immune activation in these patients. Until now there are no published studies implicating TLRs 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.
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|Ninkovic, Jana; Jana, Ninkovic; Anand, Vidhu et al. (2016) Differential effects of gram-positive and gram-negative bacterial products on morphine induced inhibition of phagocytosis. Sci Rep 6:21094|
|Banerjee, Santanu; Ninkovic, Jana; Meng, Jingjing et al. (2015) Morphine compromises bronchial epithelial TLR2/IL17R signaling crosstalk, necessary for lung IL17 homeostasis. Sci Rep 5:11384|
|Meng, Jingjing; Sindberg, Gregory M; Roy, Sabita (2015) Disruption of gut homeostasis by opioids accelerates HIV disease progression. Front Microbiol 6:643|
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