The HIV-1 transgenic rat, which incorporates a replication-defective HIV-1 genome, develops a number of the immunological and clinical manifestations of human HIV disease, including nervous system involvement. Neurological disease in HIV infection has been associated with damage to nervous system tissue induced by proinflammatory cytokines and other soluble factors that are released by activated mononuclear cells. These effects have been observed to be enhanced in opioid users. Retinoids have been demonstrated to suppress such immune activity, and, in studies of HIV-1 infection, can suppress replication of virus in infected mononuclear cell lines. The cellular effects of vitamin A are mediated by specific binding to retinoic acid receptor (RAR) and retinoid X receptor (RXR). We have previously demonstrated that RAR and RXR activation can suppress proinflammatory cytokine (TNF-a) production by human cell lines and that morphine can inhibit RXR-mediated TNF-a suppression. RXR activation also increased mu opioid receptor (MOR) expression. The clinical implications of these observations and the mechanisms that underlie these effects are unclear. Therefore, in this grant we will examine the effects of retinoids using the HIV-1 transgenic rat model.
The aims of this proposal are to (1) To assess the effects of retinoid agonists and antagonists and morphine on proinflammatory responses by mononuclear cells from the HIV-1 transgenic and control rats in vitro;(2) To examine the effects of activation and exposure to retinoid agonists and antagonists and morphine on MOR expression by immune cells from transgenic and control rats;(3) To examine the effects of retinoid agonists and antagonists and morphine on HIV-1 gene expression by immune cells from transgenic and control rats;and (4) To examine the effects of vitamin A deficiency and morphine on the clinical status of HIV-1 transgenic and control rats. These studies will be useful for better understanding the role of retinoid metabolism and opioids in the pathogenesis of HIV infection in general and, more specifically, in the occurrence of nervous system disease in drug users.
|Davis, Matthew J; Khan, Adnan; Royal 3rd, Walter (2013) Progressive multifocal leukoencephalopathy as the first manifestation of occult sarcoidosis: case report and review of the literature. Neurologist 19:26-9|
|Khanna, A; Guo, M; Mehra, M et al. (2013) Inflammation and oxidative stress induced by cigarette smoke in Lewis rat brains. J Neuroimmunol 254:69-75|
|Royal 3rd, Walter; Zhang, Li; Guo, Ming et al. (2012) Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat. J Neuroimmunol 247:16-24|
|Guo, Ming; Bryant, Joseph; Sultana, Shireen et al. (2012) Effects of vitamin A deficiency and opioids on parvalbumin + interneurons in the hippocampus of the HIV-1 transgenic rat. Curr HIV Res 10:463-8|
|Sultana, Shireen; Li, Huifen; Puche, Adam et al. (2010) Quantitation of parvalbumin+ neurons and human immunodeficiency virus type 1 (HIV-1) regulatory gene expression in the HIV-1 transgenic rat: effects of vitamin A deficiency and morphine. J Neurovirol 16:33-40|
|June, Harry L; Tzeng Yang, Andrew Rong Song; Bryant, Joseph L et al. (2009) Vitamin A deficiency and behavioral and motor deficits in the human immunodeficiency virus type 1 transgenic rat. J Neurovirol 15:380-9|