Autonomic Neuropathy Is Associated with An Increase in Type-1 Cytokines in People Living With HIV

ABSTRACT Purpose Pre-clinical studies have demonstrated direct influences of the autonomic nervous system (ANS) on the immune system. However, it remains unclear if ANS-immune connections delineated in pre-clinical studies underlie the relationship between autonomic dysregulation and chronic inflammatory diseases in patients with HIV. This study had three aims: 1.) Examine the relationship between IL-6 and the parasympathetic/vagal component of baroreflex sensitivity (BRS-V) in people with HIV; 2.) Determine if the subtype and severity of HIV-autonomic neuropathy (AN) would predict distinct immunotypes; 3.) Compare the burden of non-AIDS-related co-morbidities between immunotypes. Methods 79 adults with well-controlled HIV underwent a standard battery of autonomic function tests summarized as the Composite Autonomic Severity Score and vagal and adrenergic baroreflex sensitivity (BRS-V and BRS-A). 1 Levels of immune biomarkers were measured in all participants using the Target 96 Inflammation Panel on the Olink proteomics platform and immunotypes were identified using unbiased, non-negative matrix factorization. Mass cytometry (CyTOF) was completed on a subset of participants with and without autonomic neuropathy (N = 10). Results Reduced BRS-V predicted higher levels of IL-6 (p=0.002). A pro-inflammatory immunotype defined by elevations in type 1 cytokines (IL-6, IL-17) and increased numbers of CD8+ T-cells was associated with autonomic neuropathy characterized by deficits in sympathetic nervous system activity (aOR=4.7, p=0.017). This pro-inflammatory immunotype was older with a greater burden of co-morbidities. Conclusion Deficits in the parasympathetic/cardiovagal and the sympathetic nervous system are associated with inflammation and disease burden in people living with HIV. Future longitudinal research is needed to examine causality.