The Veterans Healthcare Administration (VHA) treats more than 26,000 individuals with HIV infection, making it the largest provider of care to HIV-infected individuals in the U.S. Neurological complications occur commonly in HIV infection, with over 40% of individuals being at risk for developing HIV-related neurocognitive impairment (NCI). Therefore, it is likely that a large number of Veterans experience symptoms related to NCI, which overall responds poorly to treatment with antiretroviral drugs. Factors that underlie the development of NCI include neuronal dysfunction due to enhanced production of proinflammatory cytokines (e.g., TNF-? and IL-1?) and other inflammatory mediators that are secreted by HIV-infected cells in the brain. Astrocytes make up the largest percentage of cells in the brain and, when infected by HIV-1, secrete proinflammatory factors that can potentially have significant detrimental effects on the brain. In this proposal we will examine the potential effects of nicotinamide adenine dinucleotide (NAD) metabolism and activation of the glycohydrolase CD38, the energy sensing molecule 5' AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?) and the sirtuin SIRT1 in suppressing nervous system inflammation and other neuropathological abnormalities mediated by infection and activation of astrocytes. For these studies we will utilize two transgenic rat models of HIV-1 infection. One is a well- established model, developed on a wild-type F344 Fischer rat background (the HIV1Tg rat) and the other, developed more recently, is on a on a nude Fisher rat background (the HIV1TgNu+ rat); which provides a model of HIV infection in the presence of severe immunodeficiency. The studies proposed in this Merit will be performed utilizing F344 and F344 nude (F344Nu+) rat primary astrocytes transfected with a plasmid containing an insert that is identical to transgene that is present in the transgenic rats as well as primary cells from the rats. Studies will be also performed in vivo using the animals. The cells and animals will be treated with activators and inhibitors of NAD, CD38, AMPK and SIRT1 to determine the effects of the agents on inflammatory response and neuropathological abnormalities that can occur. We anticipate that information obtained utilizing these innovative models and approaches will lead to the development of more effective treatments for HIV-related NCI in humans.
The Veterans Administration treats more individuals with HIV infection than any other healthcare system in the country. Neurological complications are a frequent consequence of HIV infection and are often associated with the development of potentially debilitating neurocognitive impairment. Pathologically, the brains of such individuals show evidence of multiple abnormalities including astrocytic and microglial activation, which underlie the clinical abnormalities that occur. In this proposal we propose to examine the effects of nicotinamide adenine dinucleotide (NAD) metabolism and associated activation of the energy sensing molecule 5' AMP- activated protein kinase (AMPK) and generation of new energy substrates by the sirtuin SIRT1 on the development of nervous system inflammation and other abnormalities in transgenic rat models of HIV-1 infection. We anticipate that information obtained utilizing these innovative models will lead to the development of novel approaches to treating HIV-related neurocognitive impairment in humans.
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