Cytomegalovirus-specific CD8+ T-cell responses are associated with arterial blood pressure in people living with HIV

Autoři: Vibe Ballegaard aff001;  Karin Kaereby Pedersen aff001;  Peter Brændstrup aff002;  Nikolai Kirkby aff005;  Anette Stryhn aff003;  Lars P. Ryder aff002;  Jan Gerstoft aff001;  Susanne Dam Nielsen aff001
Působiště autorů: Department of Infectious Diseases, Viro-immunology Research Unit, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark aff001;  Department of Clinical Immunology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark aff002;  Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark aff003;  Department of Hematology, Herlev University Hospital, Herlev, Denmark aff004;  Department of Medical Microbiology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article


People living with HIV (PLHIV) are at increased risk for cardiovascular disease (CVD), and immunity against cytomegalovirus (CMV) may be a contributing factor. We hypothesized that enhanced T-cell responses against CMV and CMV-IgG antibody-levels are associated with higher arterial blood pressure in PLHIV. We assessed serum CMV-IgG, systolic- (SBP) and diastolic- (DBP) blood pressure, pulse pressure (PP), traditional risk factors, activated CD8+ T-cells (CD38+HLA-DR+), senescent CD8+ T-cells (CD28-CD57+) and interleukin-6 (IL-6) in 60 PLHIV and 31 HIV-uninfected controls matched on age, gender, education and comorbidity. In PLHIV, expression of interleukin-2, tumor necrosis factor-α and interferon-γ was measured by intracellular-cytokine-staining after stimulation of T-cells with CMV-pp65 and CMV-gB. Associations between CMV-specific immune responses and hypertension, SBP, DBP or PP were assessed by multivariate logistic and linear regression models adjusted for appropriate confounders. The median age of PLHIV was 47 years and 90% were male. Prevalence of hypertension in PLHIV was 37% compared to 55% of HIV-uninfected controls. CMV-specific CD8+ T-cell responses were independently associated with higher PP (CMV-pp65; β = 2.29, p = 0.001, CMV-gB; β = 2.42, p = 0.001) in PLHIV. No significant differences were found with regard to individual measures of SBP and DBP. A possible weak association was found between CMV-IgG and hypertension (β = 1.33, p = 0.049) after adjustment for age, smoking and LDL-cholesterol. HIV-related factors, IL-6, CD8+ T-cell activation or CD8+ T-cell senescence did not mediate the associations, and no associations were found between CMV-specific CD4+ T-cell responses and blood pressure in PLHIV. In conclusion, increased arterial blood pressure in PLHIV may be affected by heightened CMV-specific CD8+ T-cell responses.

Klíčová slova:

Blood pressure – Cytotoxic T cells – HIV – Human cytomegalovirus – Hypertension – Immune response – Systolic pressure – T cells


1. Legarth RA, Ahlström MG, Kronborg G, Larsen CS, Pedersen C, Pedersen G, et al. Long-Term Mortality in HIV-Infected Individuals 50 Years or Older. JAIDS J Acquir Immune Defic Syndr 2016; 71:213–218. doi: 10.1097/QAI.0000000000000825 26334734

2. Rasmussen LD, May MT, Kronborg G, Larsen CS, Pedersen C, Gerstoft J, et al. Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study. Lancet HIV 2015; 2:e288–e298. doi: 10.1016/S2352-3018(15)00077-6 26423253

3. Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet 2014; 384:241–248. doi: 10.1016/S0140-6736(14)60604-8 25042234

4. Antiretroviral Therapy Cohort Collaboration TATC. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis 2010; 50:1387–96. doi: 10.1086/652283 20380565

5. Palella FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43:27–34. doi: 10.1097/01.qai.0000233310.90484.16 16878047

6. Kannel WB, Wolf PA, McGee DL, Dawber TR, McNamara P, Castelli WP. Systolic blood pressure, arterial rigidity, and risk of stroke. The Framingham study. JAMA 1981; 245:1225–9. 7206111

7. Bergersen BM, Sandvik L, Dunlop O, Birkeland K, Bruun JN. Prevalence of Hypertension in HIV-Positive Patients on Highly Active Retroviral Therapy (HAART) Compared with HAART-Naïve and HIV-Negative Controls: Results from a Norwegian Study of 721 Patients. Eur J Clin Microbiol Infect Dis 2003; 22:731–736. doi: 10.1007/s10096-003-1034-z 14610658

8. Gelpi M, Afzal S, Lundgren J, Ronit A, Roen A, Mocroft A, et al. Higher Risk of Abdominal Obesity, Elevated LDL Cholesterol and Hypertriglyceridemia, but not of Hypertension, in People Living with HIV: Results from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study. Clin Infect Dis Published Online First: 17 February 2018. doi: 10.1093/cid/ciy146 29471519

9. Baekken M, Os I, Sandvik L, Oektedalen O. Hypertension in an urban HIV-positive population compared with the general population: influence of combination antiretroviral therapy. J Hypertens 2008; 26:2126–2133. doi: 10.1097/HJH.0b013e32830ef5fb 18854751

10. Gazzaruso C, Bruno R, Garzaniti A, Giordanetti S, Fratino P, Sacchi P, et al. Hypertension among HIV patients: prevalence and relationships to insulin resistance and metabolic syndrome. J Hypertens 2003; 21:1377–82. doi: 10.1097/01.hjh.0000059071.43904.dc 12817187

11. Manner IW, Trøseid M, Oektedalen O, Baekken M, Os I. Low Nadir CD4 Cell Count Predicts Sustained Hypertension in HIV-Infected Individuals. J Clin Hypertens 2013; 15:101–106.

12. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 2010; 20:202–213. doi: 10.1002/rmv.655 20564615

13. Staras SAS, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis 2006; 43:1143–51. doi: 10.1086/508173 17029132

14. Naeger DM, Martin JN, Sinclair E, Hunt PW, Bangsberg DR, Hecht F, et al. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS One 2010; 5:e8886. doi: 10.1371/journal.pone.0008886 20126452

15. Ballegaard V, Brændstrup P, Pedersen KK, Kirkby N, Stryhn A, Ryder LP, et al. Cytomegalovirus-specific T-cells are associated with immune senescence, but not with systemic inflammation, in people living with HIV. Sci Rep 2018; 8:3778. doi: 10.1038/s41598-018-21347-4 29491459

16. Lichtner M, Cicconi P, Vita S, Cozzi-Lepri A, Galli M, Lo Caputo S, et al. CMV co-infection and risk of AIDS and non-AIDS events in a large cohort of HIV-infected patients. J Int AIDS Soc 2012; 15:18197.

17. Hsue PY, Hunt PW, Sinclair E, Bredt B, Franklin A, Killian M, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006; 20:2275–83. doi: 10.1097/QAD.0b013e3280108704 17117013

18. Masiá M, Robledano C, Ortiz de la Tabla V, Antequera P, López N, Gutiérrez F. Increased Carotid Intima-Media Thickness Associated with Antibody Responses to Varicella-Zoster Virus and Cytomegalovirus in HIV-Infected Patients. PLoS One 2013; 8:e64327. doi: 10.1371/journal.pone.0064327 23717597

19. Parrinello CM, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. J Infect Dis 2012; 205:1788–96. doi: 10.1093/infdis/jis276 22492856

20. Gkrania-Klotsas E, Langenberg C, Sharp SJ, Luben R, Khaw K-T, Wareham NJ. Seropositivity and higher immunoglobulin g antibody levels against cytomegalovirus are associated with mortality in the population-based European prospective investigation of Cancer-Norfolk cohort. Clin Infect Dis 2013; 56:1421–7. doi: 10.1093/cid/cit083 23442763

21. Roberts ET, Haan MN, Dowd JB, Aiello AE. Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am J Epidemiol 2010; 172:363–71. doi: 10.1093/aje/kwq177 20660122

22. Youn J-C, Kim JY, Jung MK, Yu HT, Park S-H, Kim I-C, et al. Analysis of cytomegalovirus-specific T-cell responses in patients with hypertension: comparison of assay methods and antigens. Clin Hypertens 2018; 24:5. doi: 10.1186/s40885-018-0090-8 29568571

23. Nieto FJ, Adam E, Sorlie P, Farzadegan H, Melnick JL, Comstock GW, et al. Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation 1996; 94:922–7. doi: 10.1161/01.cir.94.5.922 8790026

24. Wang H, Peng G, Bai J, He B, Huang K, Hu X, et al. Cytomegalovirus Infection and Relative Risk of Cardiovascular Disease (Ischemic Heart Disease, Stroke, and Cardiovascular Death): A Meta-Analysis of Prospective Studies Up to 2016. J Am Heart Assoc 2017; 6. doi: 10.1161/JAHA.116.005025 28684641

25. Gkrania-Klotsas E, Langenberg C, Sharp SJ, Luben R, Khaw K-T, Wareham NJ. Higher immunoglobulin G antibody levels against cytomegalovirus are associated with incident ischemic heart disease in the population-based EPIC-Norfolk cohort. J Infect Dis 2012; 206:1897–903. doi: 10.1093/infdis/jis620 23045624

26. Firth C, Harrison R, Ritchie S, Wardlaw J, Ferro CJ, Starr JM, et al. Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals. QJM 2016; 109:595–600. doi: 10.1093/qjmed/hcw026 27071749

27. Terrazzini N, Bajwa M, Vita S, Cheek E, Thomas D, Seddiki N, et al. A novel cytomegalovirus-induced regulatory-type T-cell subset increases in size during older life and links virus-specific immunity to vascular pathology. J Infect Dis 2014; 209:1382–92. doi: 10.1093/infdis/jit576 24203779

28. Li Z, Tang Y, Tang N, Feng Q, Zhong H, Liu Y, et al. High anti-human cytomegalovirus antibody levels are associated with the progression of essential hypertension and target organ damage in Han Chinese population. PLoS One 2017; 12:e0181440. doi: 10.1371/journal.pone.0181440 28837559

29. Haarala A, Kähönen M, Lehtimäki T, Aittoniemi J, Jylhävä J, Hutri-Kähönen N, et al. Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study. Clin Exp Immunol 2012; 167:309–16. doi: 10.1111/j.1365-2249.2011.04513.x 22236008

30. Yu HT, Youn J-C, Kim JH, Seong Y-J, Park S-H, Kim HC, et al. Arterial Stiffness Is Associated With Cytomegalovirus-Specific Senescent CD8+ T Cells. J Am Heart Assoc 2017; 6. doi: 10.1161/JAHA.117.006535 28847915

31. Cheng J, Ke Q, Jin Z, Wang H, Kocher O, Morgan JP, et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog 2009; 5:e1000427. doi: 10.1371/journal.ppat.1000427 19436702

32. Bolovan-Fritts CA, Trout RN, Spector SA. High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage. Blood 2007; 110:1857–1863. doi: 10.1182/blood-2007-03-078881 17519388

33. Bolovan-Fritts CA, Spector SA. Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction. Blood 2008; 111:175–182. doi: 10.1182/blood-2007-08-107730 17895402

34. Pachnio A, Ciaurriz M, Begum J, Lal N, Zuo J, Beggs A, et al. Cytomegalovirus Infection Leads to Development of High Frequencies of Cytotoxic Virus-Specific CD4+ T Cells Targeted to Vascular Endothelium. PLOS Pathog 2016; 12:e1005832. doi: 10.1371/journal.ppat.1005832 27606804

35. Pedersen KK, Pedersen M, Gaardbo JC, Ronit A, Hartling HJ, Bruunsgaard H, et al. Persisting inflammation and chronic immune activation but intact cognitive function in HIV-infected patients after long-term treatment with combination antiretroviral therapy. J Acquir Immune Defic Syndr 2013; 63:272–9. doi: 10.1097/QAI.0b013e318289bced 23392469

36. Pedersen KK, Manner IW, Seljeflot I, Kvale D, Os I, Gerstoft J, et al. Monocyte activation, but not microbial translocation, is independently associated with markers of endovascular dysfunction in HIV-infected patients receiving cART. J Acquir Immune Defic Syndr 2014; 67:370–4. doi: 10.1097/QAI.0000000000000339 25226210

37. Pedersen KK, Pedersen M, Trøseid M, Gaardbo JC, Lund TT, Thomsen C, et al. Microbial translocation in HIV infection is associated with dyslipidemia, insulin resistance, and risk of myocardial infarction. J Acquir Immune Defic Syndr 2013; 64:425–33. doi: 10.1097/QAI.0b013e31829f919d 23797689

38. Pedersen KK, Eiersted MR, Gaardbo JC, Pedersen M, Gerstoft J, Troseid M, et al. Lower self-reported Quality of Life in HIV-infected patients on cART and with low co-morbidity compared to healthy controls. J Acquir Immune Defic Syndr Published Online First: 21 May 2015. doi: 10.1097/QAI.0000000000000697 26017659

39. Ballegaard V, Ralfkiaer U, Pedersen KK, Hove M, Koplev S, Brændstrup P, et al. MicroRNA-210, MicroRNA-331, and MicroRNA-7 are differentially regulated in treated HIV-1-infected individuals and are associated with markers of systemic inflammation. J Acquir Immune Defic Syndr 2017; 74. doi: 10.1097/QAI.0000000000001191 27749601

40. Pedersen M, Pedersen KK, Bruunsgaard H, Krabbe KS, Thomsen C, Færch K, et al. Cognitive Functions in Middle Aged Individuals Are Related to Metabolic Disturbances and Aerobic Capacity: A Cross-Sectional Study. PLoS One 2012; 7:e51132. doi: 10.1371/journal.pone.0051132 23251434

41. WHO. Waist Circumference and Waist-Hip Ratio: Report of a WHO Expert Consultation. World Heal Organ 2008;:8–11.

42. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507–20. doi: 10.1001/jama.2013.284427 24352797

43. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study. Circulation 1999; 100:354–60. doi: 10.1161/01.cir.100.4.354 10421594

44. Maecker HT, Maino VC. Analyzing t-cell responses to cytomegalovirus by cytokine flow cytometry. Hum Immunol 2004; 65:493–499. doi: 10.1016/j.humimm.2004.02.004 15172449

45. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 2005; 202:673–85. doi: 10.1084/jem.20050882 16147978

46. Horton H, Thomas EP, Stucky JA, Frank I, Moodie Z, Huang Y, et al. Optimization and validation of an 8-color intracellular cytokine staining (ICS) assay to quantify antigen-specific T cells induced by vaccination. J Immunol Methods 2007; 323:39–54. doi: 10.1016/j.jim.2007.03.002 17451739

47. Loeth N, Assing K, Madsen HO, Vindeløv L, Buus S, Stryhn A. Humoral and cellular CMV responses in healthy donors; identification of a frequent population of CMV-specific, CD4+ T cells in seronegative donors. PLoS One 2012; 7:e31420. doi: 10.1371/journal.pone.0031420 22347475

48. Braendstrup P, Mortensen BK, Justesen S, Osterby T, Rasmussen M, Hansen AM, et al. Identification and HLA-tetramer-validation of human CD4+ and CD8+ T cell responses against HCMV proteins IE1 and IE2. PLoS One 2014; 9:e94892. doi: 10.1371/journal.pone.0094892 24760079

49. Lachmann R, Bajwa M, Vita S, Smith H, Cheek E, Akbar A, et al. Polyfunctional T cells accumulate in large human cytomegalovirus-specific T cell responses. J Virol 2012; 86:1001–9. doi: 10.1128/JVI.00873-11 22072753

50. Bajwa M, Vita S, Vescovini R, Larsen M, Sansoni P, Terrazzini N, et al. Functional Diversity of Cytomegalovirus-Specific T Cells Is Maintained in Older People and Significantly Associated With Protein Specificity and Response Size. J Infect Dis 2016; 214:1430–1437. doi: 10.1093/infdis/jiw371 27521364

51. Abate D, Saldan A, Mengoli C, Fiscon M, Silvestre C, Fallico L, et al. Comparison of cytomegalovirus (CMV) enzyme-linked immunosorbent spot and CMV quantiferon gamma interferon-releasing assays in assessing risk of CMV infection in kidney transplant recipients. J Clin Microbiol 2013; 51:2501–7. doi: 10.1128/JCM.00563-13 23678073

52. Delforge ML, Desomberg L, Montesinos I. Evaluation of the new LIAISON ® CMV IgG, IgM and IgG Avidity II assays. J Clin Virol 2015; 72:42–45. doi: 10.1016/j.jcv.2015.09.002 26395519

53. Stone SF, Price P, Khan N, Moss PA, French MA. HIV patients on antiretroviral therapy have high frequencies of CD8 T cells specific for Immediate Early protein-1 of cytomegalovirus. AIDS 2005; 19:555–62. doi: 10.1097/01.aids.0000163931.68907.7e 15802973

54. Kooij KW, Schouten J, Wit FWNM, van der Valk M, Kootstra NA, Stolte IG, et al. Difference in Aortic Stiffness Between Treated Middle-Aged HIV Type 1-Infected and Uninfected Individuals Largely Explained by Traditional Cardiovascular Risk Factors, With an Additional Contribution of Prior Advanced Immunodeficiency. J Acquir Immune Defic Syndr 2016; 73:55–62. doi: 10.1097/QAI.0000000000001024 27513572

55. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of Cardiovascular Events and All-Cause Mortality With Arterial Stiffness. J Am Coll Cardiol 2010; 55:1318–1327. doi: 10.1016/j.jacc.2009.10.061 20338492

56. Shirwany NA, Zou M. Arterial stiffness: a brief review. Acta Pharmacol Sin 2010; 31:1267–1276. doi: 10.1038/aps.2010.123 20802505

57. Haider AW, Larson MG, Franklin SS, Levy D, Framingham Heart Study. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003; 138:10–6. doi: 10.7326/0003-4819-138-1-200301070-00006 12513039

58. Youn J-C, Yu HT, Lim BJ, Koh MJ, Lee J, Chang D-Y, et al. Immunosenescent CD8+ T Cells and C-X-C Chemokine Receptor Type 3 Chemokines Are Increased in Human Hypertension. Hypertension 2013; 62:126–133. doi: 10.1161/HYPERTENSIONAHA.113.00689 23716586

59. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. T cell activation predicts carotid artery stiffness among HIV-infected women. Atherosclerosis 2011; 217:207–213. doi: 10.1016/j.atherosclerosis.2011.03.011 21492857

60. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. T Cell Activation and Senescence Predict Subclinical Carotid Artery Disease in HIV-Infected Women. J Infect Dis 2011; 203:452–463. doi: 10.1093/infdis/jiq071 21220772

61. Karim R, Mack WJ, Kono N, Tien PC, Anastos K, Lazar J, et al. T-Cell Activation, Both Pre- and Post-HAART Levels, Correlates With Carotid Artery Stiffness Over 6.5 Years Among HIV-Infected Women in the WIHS. JAIDS J Acquir Immune Defic Syndr 2014; 67:349–356. doi: 10.1097/QAI.0000000000000311 25314253

62. De Socio G V., Ricci E, Maggi P, Parruti G, Pucci G, Di Biagio A, et al. Prevalence, Awareness, Treatment, and Control Rate of Hypertension in HIV-Infected Patients: The HIV-HY Study. Am J Hypertens 2014; 27:222–228. doi: 10.1093/ajh/hpt182 24077828

63. Freeman ML, Lederman MM, Gianella S. Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection. Curr HIV/AIDS Rep 2016; 13:10–19. doi: 10.1007/s11904-016-0297-9 26810437

64. Gianella S, Letendre S. Cytomegalovirus and HIV: A Dangerous Pas de Deux. J Infect Dis 2016; 214 Suppl:S67–74.

65. Li H, Margolick JB, Bream JH, Nilles TL, Langan S, Bui HT, et al. Heterogeneity of CD4+ and CD8+ T-cell Responses to Cytomegalovirus in HIV-Infected and HIV-Uninfected Men Who Have Sex With Men. J Infect Dis 2014; 210:400–404. doi: 10.1093/infdis/jiu093 24532602

66. Jacobson MA, Sinclair E, Bredt B, Agrillo L, Black D, Epling CL, et al. Antigen-specific T cell responses induced by Towne cytomegalovirus (CMV) vaccine in CMV-seronegative vaccine recipients. J Clin Virol 2006; 35:332–337. doi: 10.1016/j.jcv.2005.09.019 16387547

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