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

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. 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:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1441333
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
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Science Translational Medicine
Additional Journal Information:
Journal Volume: 9; Journal Issue: 405; Journal ID: ISSN 1946-6234
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats

Schechter, Melissa E., Andrade, Bruno B., 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, and Sereti, Irini. Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. United States: N. p., 2017. Web. doi:10.1126/scitranslmed.aam5441.
Schechter, Melissa E., Andrade, Bruno B., 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. Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. United States. doi:10.1126/scitranslmed.aam5441.
Schechter, Melissa E., Andrade, Bruno B., 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, and Sereti, Irini. Wed . "Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy". United States. doi:10.1126/scitranslmed.aam5441. https://www.osti.gov/servlets/purl/1441333.
@article{osti_1441333,
title = {Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy},
author = {Schechter, Melissa E. and Andrade, Bruno B. and He, Tianyu and Richter, George Haret and Tosh, Kevin W. and Policicchio, Benjamin B. and Singh, Amrit and Raehtz, Kevin D. and Sheikh, Virginia and Ma, Dongying and Brocca-Cofano, Egidio and Apetrei, Cristian and Tracy, Russel and Ribeiro, Ruy M. and Sher, Alan and Francischetti, Ivo M. B. and Pandrea, Ivona and Sereti, Irini},
abstractNote = {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.},
doi = {10.1126/scitranslmed.aam5441},
journal = {Science Translational Medicine},
issn = {1946-6234},
number = 405,
volume = 9,
place = {United States},
year = {2017},
month = {8}
}

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Cited by: 12 works
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Works referenced in this record:

Binding of human factor VII and VIIa to monocytes.
journal, September 1982

  • Broze, G. J.
  • Journal of Clinical Investigation, Vol. 70, Issue 3
  • DOI: 10.1172/JCI110644

Markers of Inflammation, Coagulation, and Renal Function Are Elevated in Adults with HIV Infection
journal, June 2010

  • Neuhaus, Jacqueline; Jacobs, Jr, David R.; Baker, Jason V.
  • The Journal of Infectious Diseases, Vol. 201, Issue 12
  • DOI: 10.1086/652749

Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates
journal, August 2012


Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome
journal, November 2012


Higher Levels of CRP, D-dimer, IL-6, and Hyaluronic Acid Before Initiation of Antiretroviral Therapy (ART) Are Associated With Increased Risk of AIDS or Death
journal, June 2011

  • Boulware, David R.; Hullsiek, Katherine Huppler; Puronen, Camille E.
  • The Journal of Infectious Diseases, Vol. 203, Issue 11
  • DOI: 10.1093/infdis/jir134

Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection
journal, October 2008


Thrombin selectively induces transcription of genes in human monocytes involved in inflammation and wound healing
journal, January 2014

  • Lopéz, Mercedes; Bruges, Gustavo; Crespo, Gustavo
  • Thrombosis and Haemostasis, Vol. 112, Issue 11
  • DOI: 10.1160/TH14-01-0034

Protease-activated receptors in hemostasis, thrombosis and vascular biology
journal, August 2005


The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells: Inhibitor Ixolaris prevents tissue factor signaling
journal, September 2012


Trained immunity: A program of innate immune memory in health and disease
journal, April 2016


Bidirectional Relation Between Inflammation and Coagulation
journal, June 2004


Pathogenic Features Associated with Increased Virulence upon Simian Immunodeficiency Virus Cross-Species Transmission from Natural Hosts
journal, April 2014

  • Mandell, D. T.; Kristoff, J.; Gaufin, T.
  • Journal of Virology, Vol. 88, Issue 12
  • DOI: 10.1128/JVI.03785-13

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication
journal, May 2014

  • Kristoff, Jan; Haret-Richter, George; Ma, Dongzhu
  • Journal of Clinical Investigation, Vol. 124, Issue 6
  • DOI: 10.1172/JCI75090

Thrombin generation and atherosclerosis
journal, November 2013

  • Kalz, Jana; ten Cate, Hugo; Spronk, Henri M. H.
  • Journal of Thrombosis and Thrombolysis, Vol. 37, Issue 1
  • DOI: 10.1007/s11239-013-1026-5

HIV Replication Alters the Composition of Extrinsic Pathway Coagulation Factors and Increases Thrombin Generation
journal, August 2013

  • Baker, Jason V.; Brummel‐Ziedins, Kathleen; Neuhaus, Jacqueline
  • Journal of the American Heart Association, Vol. 2, Issue 4
  • DOI: 10.1161/JAHA.113.000264

Does Inflammation Contribute to Thrombotic Events?
journal, January 2000

  • Esmon, Charles T.
  • Pathophysiology of Haemostasis and Thrombosis, Vol. 30, Issue 2
  • DOI: 10.1159/000054161

Tissue factor in blood cells and endothelial cells
journal, January 2012

  • Osterud, Bjarne
  • Frontiers in Bioscience, Vol. E4, Issue 1
  • DOI: 10.2741/e376

Coagulation and morbidity in treated HIV infection
journal, May 2014


Soluble Markers of Inflammation and Coagulation but Not T-Cell Activation Predict Non–AIDS-Defining Morbid Events During Suppressive Antiretroviral Treatment
journal, May 2014

  • Tenorio, Allan R.; Zheng, Yu; Bosch, Ronald J.
  • The Journal of Infectious Diseases, Vol. 210, Issue 8
  • DOI: 10.1093/infdis/jiu254

SIVagm Infection in Wild African Green Monkeys from South Africa: Epidemiology, Natural History, and Evolutionary Considerations
journal, January 2013


Mycobacterium tuberculosis Infection and Tissue Factor Expression in Macrophages
journal, September 2012


Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals
journal, September 2012


Glucose Transporter 1–Expressing Proinflammatory Monocytes Are Elevated in Combination Antiretroviral Therapy–Treated and Untreated HIV + Subjects
journal, November 2014

  • Palmer, Clovis S.; Anzinger, Joshua J.; Zhou, Jingling
  • The Journal of Immunology, Vol. 193, Issue 11
  • DOI: 10.4049/jimmunol.1303092

Monocytes and macrophages: developmental pathways and tissue homeostasis
journal, May 2014

  • Ginhoux, Florent; Jung, Steffen
  • Nature Reviews Immunology, Vol. 14, Issue 6
  • DOI: 10.1038/nri3671

Protease-activated receptor signaling in the regulation of inflammation
journal, January 2004


Using the Pathogenic and Nonpathogenic Nonhuman Primate Model for Studying Non-AIDS Comorbidities
journal, January 2015


HIV and Inflammation: Mechanisms and Consequences
journal, April 2012


Increased glucose transporter-1 expression on intermediate monocytes from HIV-infected women with subclinical cardiovascular disease
journal, January 2017


Role of Tissue Factor in Atherothrombosis
journal, August 2012


Inflammatory monocyte effector mechanisms
journal, September 2014


Monocytes in Coronary Artery Disease and Atherosclerosis
journal, October 2013

  • Ghattas, Angie; Griffiths, Helen R.; Devitt, Andrew
  • Journal of the American College of Cardiology, Vol. 62, Issue 17
  • DOI: 10.1016/j.jacc.2013.07.043

Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria
journal, March 2012

  • Francischetti, Ivo M. B.; Oliveira, Carlo J.; Ostera, Graciela R.
  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 32, Issue 3
  • DOI: 10.1161/ATVBAHA.111.240291

Markers of coagulation and inflammation often remain elevated in ART-treated HIV-infected patients
journal, January 2014


HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group
journal, January 2012

  • High, Kevin P.; Brennan-Ing, Mark; Clifford, David B.
  • JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol. 60
  • DOI: 10.1097/QAI.0b013e31825a3668

Immunologic predictors of coronary artery calcium progression in a contemporary HIV cohort
journal, January 2014


Monocyte-Activation Phenotypes Are Associated With Biomarkers of Inflammation and Coagulation in Chronic HIV Infection
journal, May 2014

  • Wilson, Eleanor M. P.; Singh, Amrit; Hullsiek, Katherine Huppler
  • The Journal of Infectious Diseases, Vol. 210, Issue 9
  • DOI: 10.1093/infdis/jiu275

Elevated Levels of Monocyte Activation Markers Are Associated With Subclinical Atherosclerosis in Men With and Those Without HIV Infection
journal, October 2014

  • McKibben, Rebeccah A.; Margolick, Joseph B.; Grinspoon, Steven
  • The Journal of Infectious Diseases, Vol. 211, Issue 8
  • DOI: 10.1093/infdis/jiu594

Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques
journal, January 2016


Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection
journal, March 2011

  • Sandler, Netanya G.; Wand, Handan; Roque, Annelys
  • The Journal of Infectious Diseases, Vol. 203, Issue 6
  • DOI: 10.1093/infdis/jiq118

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS
journal, January 2013

  • Marchetti, Giulia; Tincati, Camilla; Silvestri, Guido
  • Clinical Microbiology Reviews, Vol. 26, Issue 1
  • DOI: 10.1128/CMR.00050-12

Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild
journal, March 2014

  • Ma, D.; Jasinska, A. J.; Feyertag, F.
  • Journal of Virology, Vol. 88, Issue 10
  • DOI: 10.1128/JVI.03606-13

Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers
journal, January 2013


Metabolic Reprogramming of Macrophages: GLUCOSE TRANSPORTER 1 (GLUT1)-MEDIATED GLUCOSE METABOLISM DRIVES A PROINFLAMMATORY PHENOTYPE
journal, February 2014

  • Freemerman, Alex J.; Johnson, Amy R.; Sacks, Gina N.
  • Journal of Biological Chemistry, Vol. 289, Issue 11
  • DOI: 10.1074/jbc.M113.522037

Changes in Inflammatory and Coagulation Biomarkers: A Randomized Comparison of Immediate versus Deferred Antiretroviral Therapy in Patients With HIV Infection
journal, January 2011

  • Baker, Jason V.; Neuhaus, Jacqueline; Duprez, Daniel
  • JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol. 56, Issue 1
  • DOI: 10.1097/QAI.0b013e3181f7f61a

CD14++CD16+ Monocytes Independently Predict Cardiovascular Events
journal, October 2012

  • Rogacev, Kyrill S.; Cremers, Bodo; Zawada, Adam M.
  • Journal of the American College of Cardiology, Vol. 60, Issue 16
  • DOI: 10.1016/j.jacc.2012.07.019

Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity
journal, March 2008

  • Shpacovitch, V.; Feld, M.; Hollenberg, M. D.
  • Journal of Leukocyte Biology, Vol. 83, Issue 6
  • DOI: 10.1189/jlb.0108001

Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation
journal, January 2010


Where the Wild Things Are: Pathogenesis of SIV Infection in African Nonhuman Primate Hosts
journal, January 2010


Antithrombotic properties of Ixolaris, a potent inhibitor of the extrinsic pathway of the coagulation cascade
journal, January 2006

  • Nazareth, Rômulo; Tomaz, Luana; Ortiz-Costa, Susana
  • Thrombosis and Haemostasis, Vol. 96, Issue 07
  • DOI: 10.1160/TH06-02-0105

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    Deciphering Biological Processes at the Tick-Host Interface Opens New Strategies for Treatment of Human Diseases
    journal, July 2019

    • Štibrániová, Iveta; Bartíková, Pavlína; Holíková, Viera
    • Frontiers in Physiology, Vol. 10
    • DOI: 10.3389/fphys.2019.00830

    Deciphering Biological Processes at the Tick-Host Interface Opens New Strategies for Treatment of Human Diseases
    journal, July 2019

    • Štibrániová, Iveta; Bartíková, Pavlína; Holíková, Viera
    • Frontiers in Physiology, Vol. 10
    • DOI: 10.3389/fphys.2019.00830