Research Project
10160501
ABSTRACT Cerebral small vessel disease (CSVD) and transient ischemic attacks (TIAs) are emerging comorbidities of neuroHIV. The application is built on the most important findings from the previous funding cycle and will evaluate the mechanistic events underlying the impact of HIV on CSVD in relationship to TIA outcome and recovery (Aim 1) and HIV reactivation in the CNS and its egress into the periphery (Aim 2). The significance of the proposed work drives primarily from the facts that CSVD is the major cause of cognitive impairment, contributes to 25% of incidents of brain ischemia, and more than doubles the risk of their recurrence. In addition, the risk of developing transient ischemic attacks (TIAs) or other forms of brain ischemia is estimated to be at least 1.5-2-fold higher in HIV-positive individuals compared to the control population. The central hypothesis of the present proposal is that HIV-induced cerebral vascular pathology drives neuroimmune activation, predisposing HIV-infected brains to the development of CSVD and more severe TIA outcomes. Mechanistically, we will focus on the impact of HIV and CSVD on reprogramming of mitochondria and the role of dysfunctional mitochondria in these events. Our important preliminary data indicates that HIV can be reactivated from latently infected HIV brains, and we show for the first time that this process also occurs as the result of brain ischemia. We will further explore these processes, and will evaluate if reactivated HIV in the CNS can egress into the periphery. The proposed research is highly innovative by its focus on novel mechanisms underlying vascular comorbidities, such as CSVD and TIAs, in the HIV-infected brain. When completed, our application will provide critical insight into the role of HIV in CSVD and TIA development. In addition, our research will provide important information about the reactivation HIV from the brain and seeding into the periphery as the result of brain ischemia. The proposed studies are innovative and are likely to identify novel opportunities for therapeutic intervention.
