Research ArticleHIV

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

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Science Translational Medicine  30 Aug 2017:
Vol. 9, Issue 405, eaam5441
DOI: 10.1126/scitranslmed.aam5441

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Curbing complications in chronic HIV

HIV-infected patients who have viral suppression due to treatment are still at enhanced risk of comorbidities such as neurological or cardiovascular complications, so Schechter et al. explored how inflammation and coagulation intersect in chronic HIV. To do so, they examined monocytes that express tissue factor in samples from patients or macaques infected with SIV. These monocytes appear to be crucial to coagulopathy. Treatment with a compound isolated from tick saliva, Ixolaris, can interrupt this damaging pathway. It is possible in the future that HIV patients would be treated with Ixolaris to stem some of the side effects of chronic infection.

Abstract

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.

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