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Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

Journal Article · · Science Translational Medicine
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [7];  [9];  [4];  [8];  [10];  [11];  [5];  [9];  [3];  [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
+ Show Author Affiliations
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 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.
Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
National Inst. of Health (NIH); USDOE
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1441333
Report Number(s):
LA-UR--18-20264
Journal Information:
Science Translational Medicine, Journal Name: Science Translational Medicine Journal Issue: 405 Vol. 9; ISSN 1946-6234
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (23)

The coagulation system in host defense journal May 2018
Platelet function in HIV plus dengue coinfection associates with reduced inflammation and milder dengue illness journal May 2019
Hydroxyurea alters circulating monocyte subsets and dampens its inflammatory potential in sickle cell anemia patients journal October 2019
HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies journal July 2018
Evidence for Persistent Monocyte and Immune Dysregulation After Prolonged Viral Suppression Despite Normalization of Monocyte Subsets, sCD14 and sCD163 in HIV-Infected Individuals journal December 2019
Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging journal December 2018
Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models journal November 2019
Platelets in Immune Response to Virus and Immunopathology of Viral Infections journal April 2018
Tissue Factor book January 2005
Tissue Factor book January 2019
Tissue Factor book January 2017
Tissue factor: from ???just one of the coagulation factors??? to a major player in physiology journal January 2004
P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL-10 and IL-1β in a human tonsil explant model posted_content July 2018
Multivariate Computational Analysis of Gamma Delta T cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging posted_content November 2018
P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model journal October 2018
Tissue Factor: Past, Present, and Future journal December 2009
Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis journal April 2018
Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart Association journal July 2019
High-fat diet exacerbates SIV pathogenesis and accelerates disease progression journal October 2019
Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates journal September 2018
NMR structure determination of Ixolaris and factor X(a) interaction reveals a noncanonical mechanism of Kunitz inhibition journal August 2019
Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling journal August 2019
Deciphering Biological Processes at the Tick-Host Interface Opens New Strategies for Treatment of Human Diseases journal July 2019

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