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.

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

“…HIV-1-infected patients have elevated circulating levels of LPS, which can serve to increase transcriptional activation of proinflammatory cytokines (11,50). Elevated levels of IL-1␤ are associated with many of the AANCCs seen in HIV-1-infected patients (91)(92)(93)(94). Currently, there are multiple clinical trials assessing the safety and efficacy of anti-IL-1␤ antibodies in cardiovascular disease (95,96).…”

Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates

“…In addition to acting as mechanical barriers leading to plate let aggregation, NETs may impact coagulation through other pathways. Both neutrophils and NETs can express TF (17,18), an essential activator of coagulation (19). By culturing unstimulated and stimulated neutrophils from chronically SIVinfected PTMs, we found that those generating NETs preferentially express high levels of TF ( Figure 2J).…”

The coagulation system in host defense

“…Further, the coagulation activation marker correlated with virus load and monocyte TF expression in HIV‐infected patients . Interestingly, TF expression seems to be restricted to CD14 + CD16 − CCR2 + monocytes . Thrombin mediates the crosstalk between the coagulation system and the adaptive immune system at sites of vascular injury via PAR1 increasing T cell motility and proinflammatory cytokine production .…”