Complex Autonomic Neuropathic Dysfunction Leading to Gastrointestinal and Immune Effects in People with HIV (CANDLE)

Project summary Chronic HIV infection produces pathologic inflammation which drives disease progression and contributes to the development of serious co-morbid medical conditions, even in the setting of effective combination antiretroviral therapy (CART); translocation of bacterial products across the gastrointestinal (GI) mucosa is a major antigenic stimulus for this process. Our research focuses on how HIV-associated autonomic neuropathy (HIV-AN), which is part of the spectrum of HIV-associated neuropathies, affects GI and immune function in people with HIV (PWH). This application describes a continuation of work begun as part of R01DK122853 “Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV” (2/11/2020-01/31/2025). The title of this new submission is: “Complex Autonomic Neuropathic Dysfunction Leading to Gastrointestinal and Immune Effects in People with HIV (CANDLE),” which reflects a shift away from vagal dysfunction toward a more holistic consideration of the autonomic nervous system (ANS). In the prior grant we found that: 23% of PWH experience prolonged small bowel transit time (SBTT) as assessed using a Wireless Motility Capsule (WMC); prolonged SBTT is associated with small intestinal bacterial overgrowth (SIBO); HIV-AN is associated with alterations in immune function, including elevations in IL-6; HIV-AN independently predicts morbidity and mortality; and HIV-AN has heterogenous phenotypes with variable dysfunction in different branches of the ANS. Operationally, the new project will have two components: 1) longitudinal study of 125 PWH and 50 HIV- negative controls; 2) in depth, multidimensional analysis of samples/data collected during the prior R01 which include gold standard autonomic function testing; time-stamped, continuous whole gut pressure data from the WMC; saliva and stool samples for microbiome analyses; and blood samples for analysis of immune cells (using CyTOF and scRNA-seq) and plasma immune biomarkers. Our overarching goals will be to solidify the etiologic role for HIV in the development of HIV-AN, and to understand the time course of HIV-AN development and progression; and to continue to build on our understanding of the GI-mediated and direct pathways between HIV-AN and systemic inflammation which was begun in the prior R01.