Dysregulation of Complement Components Associated with Inflammation and Coagulation in Virally Suppressed People Living with HIV (PLWH)

Abstract

Although HIV has become a manageable chronic disease with the introduction of antiretroviral therapy (ART), people living with HIV (PLWH) experience a higher prevalence of age-related non-AIDS comorbidities (NACMs), such as cardiovascular disease (CVD). PLWH often presents chronic inflammation and higher thrombogenicity, which are key contributing factors for NACM’s CVD development. The interplay between the complement system and platelets with neutrophil activation and neutrophil extracellular traps (NETs) has been a major contribution to chronic inflammation and higher thrombogenicity, but little attention has been directed to its association with virally suppressed PLWH in the context of NACM CVD. We used 40 virally suppressed HIV-seropositive plasma samples and 39 HIV-seronegative plasma samples to quantify and correlate important complement components (C2, C3a, C5a, C9) and platelet activation (von-Willebrand factor-A2 (vWF-A2), ADAMTS13, tissue factor (TF), protein C, and fibrinogen) analytes. We then used ex-vivo NET assays to see further correlations with plasma proteins in inducing NET formation. Results showed that participants had similar demographics, blood parameters, and co-morbidities, with significant differences in hepatitis B and C between groups. PLWH plasma displayed significant altered differences in complement components C2 and C5a, with both of these markers significantly strongly correlated with platelet and neutrophil NET activation markers. C2 also significantly positively correlated with chronic inflammatory markers (serum amyloid A (SAA), serum amyloid P (SAP), IL-1beta, and vascular endothelial growth factor VEGF)). Furthermore, HIV status was a predictive value of C2 and C5a concentration levels in PLWH’s plasma. PLWH’s plasma was also able to induce NETosis compared to HIV-negative plasma, showing that these soluble factors can contribute to both NETosis and non-lytic NET formation as well, and platelets specifically can facilitate NETosis. Our findings highlight the association between complement dysregulation, inflammation, and coagulation in virally suppressed PLWH’s plasma.