PROJECT SUMMARY This study will investigate the epidemiology and immunology of neurocognitive symptoms of post-acute sequelae of COVID-19 (PASC, or “long COVID”) in older people living with HIV (PWH). Cognitive decline remains a common and important complication of aging with HIV and is associated with adverse outcomes including frailty, poor quality of life, disability, and death. Lasting neurocognitive symptoms of COVID-19 may be more common in older PWH given their risk factors for PASC as well as differences in underlying immune senescence and inflammation. However, the clinical burden and immunologic phenotypes of neurocognitive symptoms of PASC in older PWH have not been described to date. This information is particularly needed in low- and middle-income countries where heterologous SARS-CoV-2 vaccinations and high COVID-19 incidence were observed. This study will examine (1) the clinical phenotypes and determinants of neuropsychiatric outcomes measures among older PWH with PASC and will seek to determine (2) the immunologic and clinical profiles of older PWH with discordant immunologic and clinical sequelae of SARS- CoV-2 infection. A nested, cross-sectional study using the rich baseline clinical data and biospecimens of the NIA-funded Longitudinal Study of HIV and Aging in Brazil will collect detailed data of COVID-19 infections, symptoms, and prior vaccination to identify older PWH with PASC. A cohort of 300 participants with and without PASC will undergo additional neurocognitive testing to describe specific cognitive phenotypes in older PWH with and without PASC. Further, we will use stored biospecimens to identify older PWH with poor immunologic response to COVID-19 infection and vaccination as well as those with and without PASC to examine differences in adaptive immune senescence and systemic measures of neuroinflammation to identify clues of the immunologic mechanisms contributing to adverse COVID-19 outcomes in this population. Located in one of the epicenters of the COVID-19 pandemic and led by experts in HIV and COVID-19 epidemiology and immunology, this study will offer novel and needed insights into a critical complication of the COVID-19 pandemic in PWH.