PROJECT SUMMARY/ABSTRACT While combination antiretroviral therapy has improved life expectancy for persons with HIV (PWH), cognitive impairment persists in at least 30% of this population. However, it remains unclear whether brain aging is accelerated, i.e. whether PWH have neurophenotypes resembling older uninfected (HIV-) controls. It is also unclear how structural and functional brain aging relate to cognitive decline or preservation in PWH. To enable the applicant to address these questions, this revised proposal includes a training plan focused on further education in HIV clinical problems and practices, infectious disease biology, data analytics, and scientific professional development. This plan includes mentored learning, clinical shadowing, didactic coursework, and continuous engagement with an experienced, multi-disciplinary mentorship team. The applicant’s long-term goals are to better characterize structure-function relationships in brain aging and neurological infectious disease as an independent investigator performing clinically relevant neuroimaging. In the Research Strategy, a multimodal MRI approach is proposed, incorporating both brain structure and function. This approach will focus on two key neural biomarkers: white matter health and network connectivity. White matter integrity will be measured with diffusion-weighted MRI (DW-MRI) from a large group of de-identified PWH (n=440) and HIV- controls (n=255). Brain connectivity will be profiled using resting-state functional MRI (rs-fMRI). DW-MRI and rs-fMRI will be used to generate brain-predicted age, a summary metric representing systemic degeneration or dysfunction. Brain-predicted age will be calculated using machine learning regression models, trained to predict participant ages from MRI. Brain-age gap (BAG), the difference between predicted and chronological age, will be obtained for all participants. The central hypothesis is that brain aging, including loss of structural integrity and network connectivity, is accelerated in PWH, represented by elevated BAG among older PWH vs. HIV- controls. Aim 1 will test whether age-like white matter degeneration is increased in PWH, while Aim 2 will investigate whether network functional connectivity is decreased. As this population is at elevated risk for both clinical co-morbidities such as cardiovascular disease and likely to experience socioeconomic disadvantages, it is critical to quantify the contribution of such factors to brain aging. Aging with HIV is heterogenous, and many individuals present with typical or even resilient cognition, so factors predicting successful brain aging should also be identified, especially modifiable factors. Exploratory Aim 3 will model variability in brain aging among PWH as a function of clinical variables, demographic and socioeconomic factors, and neuropsychological performance. This research plan will provide insights into the origins of HIV-associated neurocognitive impairment, a major cl...