Systemic and Central Nervous System Vasculopathy in Acute HIV and After Early Antiretroviral Therapy

ABSTRACT Over 38 million people worldwide are living with HIV, and the non-communicable complications of HIV infection are a significant global health concern. People with HIV (PWH) have an increased risk of cerebrovascular disease, cognitive impairment, brain atrophy, and white matter disease despite treatment with antiretroviral therapy (ART) and viral suppression, though the mechanism behind this finding is not fully understood. While endothelial dysfunction has been demonstrated in chronic HIV cohorts even after ART initiation, endothelial function in early and acute HIV infection, and how this relates to later cerebrovascular health, has not been well defined. A better understanding of the timing and pathophysiology of vascular disease in PWH is needed to identify biomarkers for early preventative interventions in this population. Furthermore, given accelerated vasculopathy is a contributor to other neurocognitive disorders including COVID-19 cognitive impairment and vascular dementia, this work also has broader implications to improve brain health worldwide. In this R03 application, I seek to utilize a unique, well-established longitudinal cohort (SEARCH010/RV254) of people who initiate ART during acute HIV (AHI, i.e within 30 days of infection) in Thailand to characterize the pathophysiology of vascular dysfunction during acute HIV and after early ART. Based on preliminary data, we hypothesize that peripheral and central vasculopathy progress in PWH despite early ART. To test this hypothesis, we will prospectively enroll a cohort of 30 participants with AHI and 30 HIV negative controls and will systematically measure blood markers of endothelial dysfunction and reactive hyperemia index (a non-invasive measure of endothelial function) during AHI and longitudinally for two years (96 weeks). We will also perform automated white matter hyperintensity (WMH) burden quantification on brain MRIs performed at week 0 (AHI) and at week 96 in these participants. We will then identify if blood biomarkers and reactive hyperemia index measurements associate with white matter disease progression at week 96. We will also examine associations between blood and imaging markers of vascular dysfunction and cognitive test scores at week 0 and week 96. The PI Dr. Holroyd is a neuroimmunology and neuroinfectious diseases trained clinician-scientist with expertise in translational research on the neurologic complications of viral infections such as HIV. The goal of this work is to gather novel exploratory data elucidating the pathophysiology of vascular dysfunction during very early HIV infection, and to identify easily measurable biomarkers that predict PWH at high risk of cerebrovascular disease to design subsequent studies to test early preventative interventions to promote brain health in this population.