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Title: Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. Thus, 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 ofmore » 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.« less
Authors:
ORCiD logo [1] ; ORCiD logo [2] ; ORCiD logo [3] ;  [4] ; ORCiD logo [5] ; ORCiD logo [6] ; ORCiD logo [7] ;  [8] ; ORCiD logo [7] ;  [9] ; ORCiD logo [4] ; ORCiD logo [8] ; ORCiD logo [10] ; ORCiD logo [11] ; ORCiD logo [5] ; ORCiD logo [9] ;  [3] ; ORCiD logo [7]
  1. Leidos Biomedical Research, Inc., Frederick, MD (United States). Frederick National Lab. for Cancer Research and Clinical Research Directorate/Clinical Monitoring Research Program
  2. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases, Immunobiology Section and Lab. of Parasitic Diseases; Oswaldo Cruz Foundation, Salvador (Brazil). Inst. Goncalo Moniz; Jose Silveira Foundation, Salvador (Brazil). Brazilian Inst. for Tuberculosis Research and Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative; Univ. of Cape Town (South Africa). Wellcome Centre for Infectious Disease Research in Africa and Inst. of Infectious Disease and Molecular Medicine; Vanderbilt Univ., Nashville, TN (United States). Division of Infectious Diseases and Dept. of Medicine
  3. Univ. of Pittsburgh, PA (United States). School of Medicine, Center for Vaccine Research and Dept. of Pathology
  4. Univ. of Pittsburgh, PA (United States). School of Medicine and Center for Vaccine Research
  5. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases, Immunobiology Section and Lab. of Parasitic Diseases
  6. Univ. of Pittsburgh, PA (United States). School of Medicine and Graduate School of Public Health, Center for Vaccine Research and Dept. of Infectious Diseases and Microbiology
  7. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy, Infectious Diseases, HIV Pathogenesis Section and Lab. of Immunoregulation
  8. Univ. of Pittsburgh, PA (United States). School of Medicine, Center for Vaccine Research and Dept. of Microbiology and Molecular Genetics
  9. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases and Lab. of Malaria and Vector Research
  10. Univ. of Vermont, Burlington, VT (United States). Robert Larner College of Medicine and Dept. of Pathology and Lab. Medicine
  11. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of Lisbon (Portugal). Faculty of Medicine and Lab. of Mathematical and Theoretical Biology
Publication Date:
Report Number(s):
LA-UR-18-20264
Journal ID: ISSN 1946-6234
Grant/Contract Number:
AC52-06NA25396; R01HL117715-10S1; HHSN261200800001E; R01 HL123096; RO1 HL117715; R01 AI119346; R01AI104373
Type:
Accepted Manuscript
Journal Name:
Science Translational Medicine
Additional Journal Information:
Journal Volume: 9; Journal Issue: 405; Journal ID: ISSN 1946-6234
Publisher:
AAAS
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biological Science
OSTI Identifier:
1441333