Inflammatory monocytes expressing tissue factor drive SIV and HIV-coagulopathy

Abstract

In human immunodeficiency virus (HIV) infection, persistent inflammation despite effective antiretroviral therapy (ART) is linked to increased risk of non-infectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. In this study, we identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with upregulated innate immune markers as well as evidence of robust production of multiple proinflammatory cytokines including IL-1β, TNF-α, and IL-6 ex vivo and in vitro upon LPS stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with SIV-related coagulopathy in the progressive (pigtail macaques) but not the non-pathogenic (African Green Monkeys) SIV infection model. Lastly, Ixolaris, an anti-coagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to toll-like receptor (TLR) stimulation. Strikingly, in vivo treatment of chronically infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.