| Description | Andrade, Bruno de Bezerril Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil 1Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical
Research Inc., Frederick National Laboratory for Cancer Research, Frederick,
MD 21701, USA. 2Immunobiology Section, Laboratory of Parasitic Diseases, National
Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
MD20892, USA. 3Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710,
Brazil. 4Multinational Organization Network Sponsoring Translational and Epidemiological
Research (MONSTER) Initiative, Instituto Brasileiro para a Investigação da
Tuberculose, Fundação José Silveira, Salvador 40210-320, Brazil. 5Wellcome Centre
for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular
Medicine, University of Cape Town, Cape Town 7925, South Africa. 6Division of
Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine,
Nashville, TN 37232, USA. 7Center for Vaccine Research, School of Medicine,
University of Pittsburgh, Pittsburgh, PA 15261, USA. 8Department of Pathology,
School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. 9Department
of Infectious Diseases and Microbiology, Graduate School of Public Health,
University of Pittsburgh, Pittsburgh, PA 15261, USA. 10HIV Pathogenesis Section,
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda,MD 20892, USA. 11Department ofMicrobiology
and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA
15261, USA. 12Laboratory of Malaria and Vector Research, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
13Department of Pathology and Laboratory Medicine, The Robert Larner, M.D. College
of Medicine University of Vermont, Burlington, VT 05405, USA. 14Theoretical Biology
and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87544, USA.
15Laboratório de Biomatemática, Faculdade de Medicina, Universidade de Lisboa,
Lisboa 1649-028, Portugal. | pt_BR |
| 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. | pt_BR |
