In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious 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. 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 up-regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor–α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)–related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant 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 stimulation. Strikingly, in vivo treatment of SIV-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.

在艾滋病毒感染中，尽管进行了有效的抗逆转录病毒治疗，但持续的炎症与心血管和血栓栓塞性疾病等非感染性慢性并发症的风险增加有关。需要更好地了解 HIV 感染的炎症和凝血途径，以优化临床护理。单核细胞活化和凝血标志物独立预测与非艾滋病事件相关的发病率和死亡率。我们鉴定了表达组织因子 (TF) 的特定单核细胞子集，在病毒学抑制后持续存在，并通过激活因子 X 触发凝血级联。这个表达 TF 的单核细胞子集具有独特的基因特征，具有上调的先天免疫标记物和证据在脂多糖刺激下，离体和体外大量产生多种促炎细胞因子，包括白细胞介素-1β (IL-1β)、肿瘤坏死因子-α (TNF-α) 和 IL-6。我们在非人灵长类动物模型中验证了我们的发现，表明表达 TF 的炎症单核细胞与进行性[猪尾猕猴 (PTM)] 中的猿猴免疫缺陷病毒 (SIV) 相关凝血病相关，但与非致病性（非洲绿猴）SIV 中无关。感染模型。最后，Ixolaris 是一种抑制 TF 通路的抗凝剂，经过测试，在体外 HIV 和 SIV 感染中有效阻断功能性 TF 活性，而不影响单核细胞对 Toll 样受体刺激的反应。引人注目的是，用 Ixolaris 体内治疗 SIV 感染的 PTM 与 D-二聚体和免疫激活的显着降低相关。这些数据表明，表达 TF 的单核细胞处于慢性 HIV 和 SIV 感染中炎症和凝血的中心，可能代表潜在的治疗靶点。