PROJECT SUMMARY HIV-associated neurocognitive disorders (HAND) remain prevalent in the current era of combination antiretroviral therapy. Despite the persistence of HAND, the pathogenesis of neurocognitive impairment in HIV is poorly understood. Increasing attention has been paid to the role of cerebrovascular injury in HAND. We hypothesize that impaired cerebral endothelial function in the setting of cerebral small vessel disease is a contributing factor to the development of neurocognitive impairment in HIV-infected individuals. In China, where the number of diagnosed cases of HIV infection is on the rise and the burden of cerebrovascular disease is high, understanding the association between cerebrovascular disease and HAND is particularly relevant. This planning grant brings together researchers from the United States and China to build sustainable capacity to conduct research on HAND in a resource-limited setting in China in order to reach our long-term goal of developing strategies to risk stratify, prevent and treat neurocognitive impairment in HIV. We will leverage an existing collaboration between the University of California, San Francisco Department of Neurology and the Peking Union Medical College Hospital Department of Infectious Diseases, in addition to the research infrastructure of the China AIDS Clinical Trials Group, to implement a pilot study aimed at: (1) estimating the association of HIV infection with transcranial Doppler ultrasound (TCD)-assessed cerebral endothelial function measured by cerebral vasoreactivity and (2) evaluating the correlation between cerebral vasoreactivity and markers of brain injury, including small vessel disease, on neuroimaging in a cross-section of treated, virally suppressed, older HIV-infected individuals and demographically-matched uninfected controls; (3) estimating the association of cerebral vasoreactivity with HAND and cognitive decline in a longitudinal cohort of treated, virally suppressed, older HIV-infected individuals and demographically-matched uninfected controls; and (4) developing human resources and infrastructure to conduct clinical research on HAND in Yunnan, China by training local staff in the performance of TCD and neuropsychological testing and in clinical research methods, developing and refining study procedures for participant recruitment, data collection and data management, and promoting rigorous research practices through use of standardized protocols and quality assurance. The data and experience generated from this pilot study will lay the foundation for a definitive R01-funded longitudinal cohort study investigating cerebrovascular mechanisms of HAND in China with the goal of identifying potential preclinical markers of disease, determining the correlation between cerebral endothelial function and disease severity and progression, and testing the efficacy of interventions that improve cerebral endothelial function on HAND for use in HIV populations in China, the US and worldwide.

PROJECT NARRATIVE The proposed study will estimate the association of cerebral endothelial function, measured by cerebral vasoreactivity, and neurocognitive impairment in Chinese HIV-infected individuals using research tools that can be implemented in low and middle-income countries. Data and experience obtained from this planning grant will provide us with essential insights into potential cerebrovascular mechanisms underlying HIV-associated neurocognitive disorders (HAND) and will lay the foundation for future collaborations aimed at identifying preclinical markers of disease, determining the correlation between cerebral endothelial function and HAND severity and progression and assessing the impact of interventions that improve cerebral endothelial function on HAND for use in HIV populations in China, the US and worldwide.