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https://www.arca.fiocruz.br/handle/icict/21112
INFLAMMATORY MONOCYTES EXPRESSING TISSUE FACTOR DRIVE SIV AND HIV COAGULOPATHY
Autor(es)
Schechter, Melissa E
Andrade, Bruno de Bezerril
He, Tianyu
Richter, George Haret
Tosh, Kevin W
Policicchio, Benjamin B
Singh, Amrit
Raehtz, Kevin D
Sheikh, Virginia
Ma, Dongying
Brocca-Cofano, Egidio
Apetrei, Cristian
Tracy, Russel
Ribeiro, Ruy M
Sher, Alan
Francischetti, Ivo M B
Pandrea, Ivona
Sereti, Irini
Andrade, Bruno de Bezerril
He, Tianyu
Richter, George Haret
Tosh, Kevin W
Policicchio, Benjamin B
Singh, Amrit
Raehtz, Kevin D
Sheikh, Virginia
Ma, Dongying
Brocca-Cofano, Egidio
Apetrei, Cristian
Tracy, Russel
Ribeiro, Ruy M
Sher, Alan
Francischetti, Ivo M B
Pandrea, Ivona
Sereti, Irini
Afiliação
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Múltipla – ver em Notas
Múltipla – ver em Notas
Resumo em Inglês
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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