Neurological complications occur commonly in HIV infection, with over 40% of individuals being at risk for developing HIV-related neurocognitive impairment (NCI), with the numbers increasing in the era of effective antiretroviral therapy (1). 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 (2,3). Contributing to such responses is impairment metabolism mediated by nicotinamide adenine dinucleotide (NAD), which is essential for normal mitochondrial function and the production of energy substrates in cells. In this grant, we will analyze potential effects of exposure to cigarette smoke (CS) and nicotine as co-factors for increasing the risk of NCI in HIV infected individuals. Cigarette smoking has been shown to alter a number of innate and adaptive immune mechanisms and can elicit cellular oxidative stress responses that can promote injury. Most marketed brands of cigarettes contain varying amounts of nicotine. In smokers, CS causes a leukocytosis and, in HIV-infected individuals, smoking is associated with higher plasma HIV viral loads and an increased mortality. It has been estimated that over 40% of HIV+ individuals are cigarette smokers (6), a number that is twice the estimated prevalence of smoking among adults in the general population (7). Nicotine, via activation of nicotinic acetylcholine receptors (nAChR), promotes cigarette smoking through its addictive properties. By activating these receptors, nicotine has been also shown to suppress immune activation and proinflammatory responses through direct effects on immune cells as well as through pathways that are mediated by activation of nicotine receptors (8-10). However, due to effects of HIV protein and with chronic nicotine exposure and upregulation of nAChR, proinflammatory responses have been observed to increase, thereby potentially contributing to CNS damage that occurs in the context of HIV infection. In previous studies in adult Lewis rats, we demonstrated that CS exposure can result in marked inflammatory and oxidative stress responses in the brains of the exposed animals (11). We have subsequently demonstrated that such effects can be also observed in HIV-1 transgenic rats, with more prominent responses developing than what are observed in corresponding wild-type animals. We also provide evidence that such responses can be driven by nicotine that is present in the CS. Activation of nAChR can also regulate cellular levels of NAD and activation of associated metabolic pathways. The potential effects of such activation in HIV infection and the generation of chronic inflammation in brain has not been previously studied. The proposed studies will be performed in vivo utilizing the transgenic rat model as well as in vitro utilizing primary astrocyte cultures that express the same HIV genes as the transgenic rat in vivo.
Neurocognitive impairment in HIV infection occurs in the context of increased proinflammatory responses in brain. Cigarette smoking, nicotine, and chronic activation of nicotinic acetyl choline receptors increase proinflammatory responses. We will examine these effects on proinflammatory response in HIV infection using a HIV-1 transgenic rat model and the potential modulation of these effects by enhancing nicotinamide adenine dinucleotide metabolism, which can suppress proinflammatory responses. 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.
| Jumare, Jibreel; El-Kamary, Samer S; Magder, Laurence et al. (2018) Plasma HIV RNA level is associated with neurocognitive function among HIV-1-infected patients in Nigeria. J Neurovirol 24:712-719 |
| Royal 3rd, Walter; Can, Adem; Gould, Todd D et al. (2018) Cigarette smoke and nicotine effects on brain proinflammatory responses and behavioral and motor function in HIV-1 transgenic rats. J Neurovirol 24:246-253 |
| Jumare, Jibreel; El-Kamary, Samer S; Magder, Laurence et al. (2018) Body Mass Index and Cognitive Function among HIV-1 Infected Individuals in China, India and Nigeria. J Acquir Immune Defic Syndr : |
