Role of hypocretin/orexin system in HIV-associated neurocognitive disorders

 

noelHIV-positive patients live longer, however approximately 50% of the HIV-infected population acquires HIV-associated neurocognitive disorders (HAND) which significantly decreases quality of life. In order to help the HIV-positive population it is necessary to find plausible biomarkers for further understanding of the pathophysiology of HAND in chronically infected subjects. Hypocretin, also known as orexin, is a neurotransmitter associated with alertness. It also regulates sleep, appetite, energy consumption, and recently it has been associated with addictive behavior. Data from our laboratory shows hcrt/ox CSF levels were higher in HIV-seropositive women from the Hispanic/Latino Longitudinal Cohort (HLLC) when compared with controls and that is was associated with HAND. Suggesting the possibility that hcrt/ox system my have a role in the pathopysiology of HAND and serve as a biomarker for HAND. The goal of this proposal is to define the underlying cause of elevated hrct/ox levels in the CSF of HIV-seropositive patients with HAND. For the purpose of this study we will use HIV-seropositive brain tissue from individuals with and without HAND from the National NeuroAIDS Tissue Consortium (NNTC). We propose the following aims: Aim 1: To determine if HIV infection alters the presence or activity of hcrt/ox –producing neurons in the lateral hypothalamus (LH) in HIV-seropositive individuals with and without HAND. Hcrt/ox neurons are localized in the LH. We hypothesize that the increased hcrt/ox levels in CSF of HIV+ patients is due to increased release of hcrt/ox from LH neurons. Aim 2: To determine if HIV-infection alters the presence of hcrt/ox receptors in the hippocampus in HIV-seropositive individuals with and without HAND. The significance of this study lies in determining the role that the hcrt/ox system plays in HAND. Hcrt/ox CSF levels could serve as a biomarker for early detection of HAND aiding the HIV-infected individual to start early treatment. This study is innovative since it focuses on the effects that HIV infection may have on the hcrt/ox system, and the role that this system may have on HAND.