Abstract Although severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is considered a respiratory pathogen, myriad neurologic complications including confusion, stroke, and neuromuscular disorders manifest during acute COVID-19. The pathophysiological mechanisms are not well understood, although evidence primarily implicates immune dysfunction, including non-specific neuroinflammation and anti-neuronal autoimmune dysregulation. Multiple common mechanisms of neuropathogenesis are implicated in SARS-CoV-2 and HIV, warranting in-depth investigation of the central nervous system (CNS) effects of co-infection with these pathogens. An urgent question is whether the 38 million PWH worldwide are at increased risk of CNS pathology associated with cognitive and mental health complications if they also acquire SARS-CoV-2. We propose to leverage the opportunity to analyze pre- and post-COVID-19 data in a unique cohort of early ART treated PWH with longitudinal multimodal CNS phenotyping to provide key information regarding the combined effects of SARS-CoV-2 and HIV on the brain. Our longitudinal RV254 study based in Bangkok, Thailand has for over 13 years prospectively collected systematic neurologic, cognitive, and mood data, as well as blood samples and optional cerebrospinal fluid (CSF) and multimodal 3 Tesla brain MRI in people during acute HIV and after suppressive antiretroviral therapy (ART). These studies have led to transformative understanding of early HIV neuropathogenesis and the benefits of early ART intervention for CNS and mental health outcomes. We hypothesize that a ‘second hit’ infection with SARS-CoV-2 – known to be associated with neuroimmune alterations, vascular damage, and neuronal injury – may incite transient or lasting detrimental changes in CNS parameters and cognitive and mental health outcomes in well treated PWH. The proposed study will analyze samples and data collected in routine longitudinal assessment of RV254 participants prior to acquiring COVID-19, then from two additional visits after COVID-19. We will collect comparison samples and data from control RV254 participants -- PWH seen over the same time intervals with no known history of COVID-19 and with no antibody evidence of COVID-19-- frequency matched based on age, gender, and educational attainment. In Aim 1, we will identify changes in CSF immune, injury, and virologic responses in PWH on ART pre- and post- COVID-19 and in comparison to controls. In Aim 2, we will examine brain structural and functional alterations in PWH on ART pre- and post-COVID-19 and in comparison to controls. In Aim 3 we will assess the trajectory of cognitive, mood, and PASC symptoms in PWH on ART before and after COVID-19 compared to controls and their relationships with the biological parameters in Aims 1 & 2. In RV254, 125 of 693 total participants have had documented COVID- 19 during their RV254 follow up, and we have already collected blood and clinical data from 81 RV254 participants pre-and post-COVID-19. Thus, longitudinal analysis of CNS parameters from pre-and post-COVID-19 and comparison non-COVID-19 controls in this deeply phenotyped RV254 cohort will provide unprecedented insight into the effects of HIV and SARS-CoV-2 coinfection in the brain.

Project Narrative Since early in the COVID-19 pandemic, some patients have described neurological symptoms during acute COVID-19 and lingering nervous system syndromes following acute infection. People with HIV (PWH) may be especially vulnerable to nervous system complications of COVID-19, including inflammation and injury in the brain as well as cognitive and mood sequelae. We propose to leverage the opportunity to analyze pre- and post-COVID-19 data in a unique cohort of virologically-suppressed, early treated PWH with longitudinal multimodal nervous system phenotyping to provide key information regarding the combined effects of SARS-CoV-2 and HIV on the brain.