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Thromb Haemost 2017; 117(06): 1141-1149
DOI: 10.1160/TH16-11-0867
Blood Cells, Inflammation and Infection
Schattauer GmbH

CCR5+ CD8 T-cell levels and monocyte activation precede the onset of acute coronary syndrome in HIV-infected patients on antiretroviral therapy

Laura Tarancon-Diez   *
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
Rebeca S. De Pablo-Bernal   *
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
Ana I. Alvarez-Ríos
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
Isaac Rosado-Sánchez
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
Beatriz Dominguez-Molina
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
Miguel Genebat
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
Yolanda M. Pacheco
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
José Luis Jiménez
3   Molecular Immunobiology Laboratory, General Universitary Hospital Gregorio Marañon, Health Research Institute Gregorio Marañon, Spanish HIV HGM BioBank, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
4   Viral and Immune Infection Unit Center, Institute of Health Carlos III, Majadahonda Campus, Molecular Immunobiology Laboratory, General Universitary Hospital Gregorio Marañon, Madrid, Spain
,
M. Ángeles Muñoz-Fernández
3   Molecular Immunobiology Laboratory, General Universitary Hospital Gregorio Marañon, Health Research Institute Gregorio Marañon, Spanish HIV HGM BioBank, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
4   Viral and Immune Infection Unit Center, Institute of Health Carlos III, Majadahonda Campus, Molecular Immunobiology Laboratory, General Universitary Hospital Gregorio Marañon, Madrid, Spain
,
Ezequiel Ruiz-Mateos   +
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
,
Manuel Leal   +
1   Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville, Seville, Spain
2   Biochemistry Department, Virgen del Rocío University Hospital, Seville, Spain
› Author Affiliations Financial support: This work was supported by Redes Tematicas de Investigacion en SIDA (ISCIII RETIC RD16/0025/0020 and RD12/0017/0037), as part of the Plan Nacional R+D+I and co-financed by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT13/0010/0028, FIS (PI13/02016; PI16/00684), Comunidad de Madrid (S-2010/BMD-2351; S-2010/BMD-2332], CYTED 214RT0482, and Programa de Investigación de la Consejería de Sanidad de la CAM to J.L.J. Proyecto de Excelencia, Consejeria de Innovacion, Ciencia y Empresa (P11-CTS-06313), Consejeria Andaluza de Salud (PI-0278–2010). L. T.-D. was supported by Instituto de Salud Carlos III, PFIS (FI14/00431). E.R.-M. and Y.M.P. were supported by the Fondo de Investigación Sanitaria through the “Miguel Servet” program [CPII014/00025 and CPII13/00037, respectively]. Y.M.P. was supported by the Consejería de Salud y Bienestar Social of Junta de Andalucía through the “Nicolás Monardes” program [C-0010/13].
Further Information

Publication History

Received: 17 November 2016

Accepted after major revision: 19 February 2017

Publication Date:
28 November 2017 (online)

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Summary

Acute coronary syndrome (ACS) is nowadays one of the leading causes of morbid-mortality in HIV-infected population, but innate and adaptive immune mechanisms preceding this event are unknown. In this work we comprehensively and longitudinally observed, by multi-parametric flow cytometry and following a case-control design, increased CCR5+CD8+ T-cells levels and monocytes expressing activation and adhesion markers in HIV-infected patients who are going to suffer ACS. In addition, we found direct associations between activated CD8+ T-cells and myeloid cells that were only statistically significant in the group of patients with ACS and in the follow up time point just before the ACS. Our data highlight the important role of CCR5 in the onset of ACS and suggest this receptor as a marker of cardiovascular risk and potential therapeutic target to prevent the development of such non-AIDS-related event in HIV-infected patients.

Note: This work was presented at the CROI 2016 conference (Boston, USA in February 2016).

Keywords

HIV - CCR5 - monocyte - vascular event - immune activation

* These authors contributed equally to this work.


+ These authors contributed equally to this work.


 

  • References

  • 1 Islam FM, Wu J, Jansson J. et al. Relative risk of cardiovascular disease among people living with HIV: A systematic review and meta-analysis. HIV Med 2012; 13: 453-468.
    PubMedGoogle Scholar
  • 2 Mary-Krause M, Cotte L, Simon A. et al. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS 2003; 17: 2479-2486.
    CrossrefPubMedGoogle Scholar
  • 3 Triant V, Lee H, Hadigan C. et al. Increased Acute Myocardial Infarction Rates and Cardiovascular Risk Factors among Patients with Human Immunodeficiency Virus Disease. J Clin Endocrinol Metab 2007; 92: 2506-2512.
    CrossrefPubMedGoogle Scholar
  • 4 Nou E, Lo J, Grinspoon SK. Inflammation, immune activation, and cardiovascular disease in HIV. AIDS 2016; 30: 1495-1509.
    CrossrefPubMedGoogle Scholar
  • 5 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12: 204-212.
    PubMedGoogle Scholar
  • 6 Rogacev KS, Cremers B, Zawada AM. et al. CD14++CD16+ monocytes independently predict cardiovascular events: A cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 2012; 60: 1512-1520.
    CrossrefPubMedGoogle Scholar
  • 7 Cipriani S, Francisci D, Mencarelli A. et al. Efficacy of the CCR5 antagonist maraviroc in reducing early, ritonavir-induced atherogenesis and advanced plaque progression in mice. Circulation 2013; 127: 2114-2124.
    CrossrefPubMedGoogle Scholar
  • 8 Burdo TH, Lo J, Abbara S. et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis 2011; 204: 1227-1236.
    CrossrefPubMedGoogle Scholar
  • 9 Merlini E, Luzi K, Suardi E. et al. T-cell phenotypes, apoptosis and inflammation in HIV+ patients on virologically effective cART with early atherosclerosis. PLoS One 2012; 7: e46073.
    CrossrefPubMedGoogle Scholar
  • 10 Longenecker CT, Funderburg NT, Jiang Y. et al. Markers of inflammation and CD8 T-cell activation, but not monocyte activation, are associated with subclinical carotid artery disease in HIV-infected individuals. HIV Med 2013; 14: 385-390.
    CrossrefPubMedGoogle Scholar
  • 11 Westhorpe CL V, Maisa A, Spelman T. et al. Associations between surface markers on blood monocytes and carotid atherosclerosis in HIV-positive individuals. Immunol Cell Biol 2014; 92: 133-138.
    CrossrefPubMedGoogle Scholar
  • 12 Anderson KM, Wilson PWF, Odell PM. et al. An updated coronary risk profile: a statement fo health professionals. Circulation 1991; 83: 356-362.
    CrossrefPubMedGoogle Scholar
  • 13 Van E aVré, Hoymans VY, Bult H. et al. Decreased number of circulating plasmacytoid dendritic cells in patients with atherosclerotic coronary artery disease. Coron Artery Dis 2006; 17: 243-248.
    CrossrefPubMedGoogle Scholar
  • 14 Niessner A, Sato K, Chaikof EL. et al. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Circulation 2006; 114: 2482-2489.
    CrossrefPubMedGoogle Scholar
  • 15 Machmach K, Leal M, Gras C. et al. Plasmacytoid Dendritic Cells Reduce HIV Production in Elite Controllers. J Virol 2012; 86: 4245-4252.
    CrossrefPubMedGoogle Scholar
  • 16 Badejo OA, Chang CC, So-Armah KA. et al. CD8+ T-cells count in acute myocardial infarction in HIV disease in a predominantly male cohort. Biomed Res Int 2015; 2015: 246870.
    PubMedGoogle Scholar
  • 17 De Pablo-Bernal RS, Ramos R, Genebat M. et al. Phenotype and Polyfunctional Deregulation Involving Interleukin 6 (IL-6)– and IL-10–Producing Monocytes in HIV-Infected Patients Receiving Combination Antiretroviral Therapy Differ From Those in Healthy Older Individuals. J Infect Dis 2016; 213: 999-1007.
    CrossrefPubMedGoogle Scholar
  • 18 Ferrando-Martinez S, Franco JM, Hernandez A. et al. Thymopoiesis in elderly human is associated with systemic inflammatory status. Age 2009; 31: 87-97.
    CrossrefPubMedGoogle Scholar
  • 19 Yun TJ, Lee JS, Machmach K. et al. Indoleamine 2,3-Dioxygenase-Expressing Aortic Plasmacytoid Dendritic Cells Protect against Atherosclerosis by Induction of Regulatory T Cells. Cell Metab 2016; 23: 852-866.
    CrossrefPubMedGoogle Scholar
  • 20 Ammirati E, Moroni F, Norata GD. et al. Markers of inflammation associated with plaque progression and instability in patients with carotid atherosclerosis. Mediators Inflamm 2015; 2015: 718329.
    PubMedGoogle Scholar
  • 21 Combadière C, Potteaux S, Rodero M. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6Chi and Ly6Clo monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 2008; 117: 1649-1657.
    CrossrefPubMedGoogle Scholar
  • 22 Liu P, Yu YRA, Spencer JA. et al. CX3CR1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden. Arterioscler Thromb Vasc Biol 2008; 28: 243-250.
    PubMedGoogle Scholar
  • 23 Butt AA, Xiaoqiang W, Budoff M. et al. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 2009; 49: 225-232.
    CrossrefPubMedGoogle Scholar
  • 24 Lichtner M, Cicconi P, Vita S. et al. Cytomegalovirus coinfection is associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients. J Infect Dis 2015; 211: 178-186.
    CrossrefPubMedGoogle Scholar
  • 25 Martin-Blondel G, Bauer J, Uro-Coste E. et al. Therapeutic use of CCR5 antagonists is supported by strong expression of CCR5 on CD8+ T cells in progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome. Acta Neuropathol 2015; 129: 463-465.
    CrossrefPubMedGoogle Scholar
  • 26 Muntinghe FLH, Verduijn M, Zuurman MW. et al. CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients. J Am Soc Nephrol 2009; 20: 1641-1649.
    CrossrefPubMedGoogle Scholar
  • 27 Shahrara S, Park CC, Temkin V. et al. RANTES modulates TLR4-induced cytokine secretion in human peripheral blood monocytes. J Immunol 2006; 177: 5077-5087.
    CrossrefPubMedGoogle Scholar
  • 28 Afzal AR, Kiechl S, Daryani YP. et al. Common CCR5-del32 frameshift mutation associated with serum levels of inflammatory markers and cardiovascular disease risk in the bruneck population. Stroke 2008; 39: 1972-1978.
    CrossrefPubMedGoogle Scholar
  • 29 Romero-Sánchez MC, Machmach K, Gonzalez-Serna A. et al. Effect of maraviroc on HIV disease progression-related biomarkers. Antimicrob Agents Che-mother 2012; 56: 5858-5864.
    CrossrefPubMedGoogle Scholar
  • 30 Gonzalez-Serna A, Genebat M, Ruiz-Mateos E. et al. Short-term maraviroc exposure, a clinical approach to decide on maraviroc prescription in HIV-1-infected treatment-naïve patients. Drug Des Devel Ther 2016; 18: 353-354.
    PubMedGoogle Scholar
  • 31 Pozo-Balado MM, Rosado-Sánchez I, Méndez-Lagares G. et al. Maraviroc contributes to the restoration of the homeostasis of regulatory T-cell subsets in anti-retroviral-naive HIV-infected subjects. Clin Microbiol Infect 2016; 22: 1-5.
    CrossrefPubMedGoogle Scholar
  • 32 Ali AS, Chopra R, Robertson J. et al. Detection of hTERT protein by flow cytometry. Leukemia 2000; 14: 2176-2181.
    CrossrefPubMedGoogle Scholar