Increased CMV IgG Antibody Titer is Associated with Non-AIDS Events Among Virologically Suppressed HIV-Positive Persons

Aimee Hodowanec, Nell S. Lurain, Supriya Krishnan, Ronald J. Bosch, Alan L. Landay

Abstract


Background: Among HIV-positive individuals, increased levels of inflammation and immune activation persist even in the setting of effective antiretroviral therapy (ART) and are associated with greater rates of non-AIDS events. The etiology of this persistent inflammation is incompletely understood.

Methods: Using a well-characterized cohort of 322 HIV-infected individuals on suppressive ART, we conducted a case-control study. Cytomegalovirus (CMV) immunoglobulin G (IgG) levels, plasma biomarkers, and T-cell phenotypes were measured/characterized from samples collected 1 year after ART initiation. Conditional logistic regression for matched case-control studies analyzed the associations of year 1 CMV-specific IgG level with the subsequent occurrence of any non-AIDS event. Correlations between continuous CMV IgG antibody levels and soluble and cellular markers were assessed.

Results: We found that higher levels of CMV IgG were associated with increased risk of non-AIDS events (OR = 1.58 per IQR [95% CI: 1.12, 2.24], P = 0.01) and with elevated soluble and cellular markers of inflammation.

Conclusions: The magnitude of the host immune response to CMV may play a role in the persistent inflammation and resultant morbid events observed in the HIV-positive population.


Keywords


HIV; cytomegalovirus (CMV); immunity; inflammation; malignancy; cardiovascular events

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References


1. Hunt PW, Cao HL, Muzoora C, Ssewanyana I, Bennett J, Emenyonu N, Kembabazi A, Neilands TB, Bangsberg DR, Deeks SG, Martin JN. Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS. 2011;25(17):2123-31. PubMed PMID: 21881481. Pubmed Central PMCID: PMC3480326. doi: 10.1097/QAD.0b013e32834c4ac1

2. Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N, Robinson J, Huang Y, Epling L, Martin JN, Deeks SG, Meinert CL, Van Natta ML, Jabs DA, Lederman MM. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis. 2014;210(8):1228-38. PubMed PMID: 24755434. Pubmed Central PMCID: PMC4192038. doi: 10.1093/infdis/jiu238

3. Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I, Douek DC. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011;203(6):780-90. PubMed PMID: 21252259. Pubmed Central PMCID: PMC3071127. doi: 10.1093/infdis/jiq118

4. Valdez H, Connick E, Smith KY, Lederman MM, Bosch RJ, Kim RS, St Clair M, Kuritzkes DR, Kessler H, Fox L, Blanchard-Vargas M, Landay A, Team ACTGP. Limited immune restoration after 3 years’ suppression of HIV-1 replication in patients with moderately advanced disease. AIDS. 2002;16(14):1859-66. PubMed PMID: 12351945.

5. Loewendorf A, Benedict CA. Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything. J Intern Med. 2010;267(5):483-501. PubMed PMID: 20433576. Pubmed Central PMCID: PMC2902254. doi: 10.1111/j.1365-2796.2010.02220.x

6. Gkrania-Klotsas E, Langenberg C, Sharp SJ, Luben R, Khaw KT, 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(12):1897-903. PubMed PMID: 23045624. doi: 10.1093/infdis/jis620

7. Gkrania-Klotsas E, Langenberg C, Sharp SJ, Luben R, Khaw KT, 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(10):1421-7. PubMed PMID: 23442763. Pubmed Central PMCID: PMC3634310. doi: 10.1093/cid/cit083

8. Parrinello CM, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Xue X, Hunt PW, Deeks SG, Hodis HN, Kaplan RC. Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. J Infect Dis. 2012;205(12):1788-96. PubMed PMID: 22492856. Pubmed Central PMCID: PMC3415890. doi: 10.1093/infdis/jis276

9. Lichtner M, Cicconi P, Vita S, Cozzi-Lepri A, Galli M, Lo Caputo S, Saracino A, De Luca A, Moioli M, Maggiolo F, Marchetti G, Vullo V, d’Arminio Monforte A. 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(2):178-86. PubMed PMID: 25081936. doi: 10.1093/infdis/jiu417

10. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, Plants J, Seth A, Wilson CC, Deeks SG, Lederman MM, Landay AL. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014;210(8):1248-59. PubMed PMID: 24795473. Pubmed Central PMCID: PMC4192039. doi: 10.1093/infdis/jiu254

11. Gianella S, Massanella M, Richman DD, Little SJ, Spina CA, Vargas MV, Lada SM, Daar ES, Dube MP, Haubrich RH, Morris SR, Smith DM, California Collaborative Treatment Group T. Cytomegalovirus replication in semen is associated with higher levels of proviral HIV DNA and CD4+ T cell activation during antiretroviral treatment. J Virol. 2014;88(14):7818-27. PubMed PMID: 24789781. Pubmed Central PMCID: 4097769. doi: 10.1128/JVI.00831-14

12. Michaelis M, Doerr HW, Cinatl J. The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia. 2009;11(1):1-9. PubMed PMID: 19107226. Pubmed Central PMCID: PMC2606113.

13. Herbein G, Kumar A. The oncogenic potential of human cytomegalovirus and breast cancer. Front Oncol. 2014;4:230. PubMed PMID: 25202681. Pubmed Central PMCID: PMC4142708. doi: 10.3389/fonc.2014.00230

14. Soderberg-Naucler C, Johnsen JI. Cytomegalovirus infection in brain tumors: A potential new target for therapy? Oncoimmunology. 2012;1(5):739-40. PubMed PMID: 22934266. Pubmed Central PMCID: PMC3429578. doi: 10.4161/onci.19441

15. Wang H, Peng G, Bai J, He B, Huang K, Hu X, Liu D. 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(7). PubMed PMID: 28684641. Pubmed Central PMCID: 5586265. doi: 10.1161/JAHA.116.005025

16. Christensen-Quick A, Vanpouille C, Lisco A, Gianella S. Cytomegalovirus and HIV Persistence: Pouring Gas on the Fire. AIDS Res Hum Retroviruses. 2017;33(S1):S23-S30. PubMed PMID: 29140108. Pubmed Central PMCID: 5684659. doi: 10.1089/aid.2017.0145

17. 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(1):10-9. PubMed PMID: 26810437. Pubmed Central PMCID: 5079703. doi: 10.1007/s11904-016-0297-9

18. Munafo MR, Davey Smith G. Robust research needs many lines of evidence. Nature. 2018;553(7689):399-401. PubMed PMID: 29368721. doi: 10.1038/d41586-018-01023-3

19. Affandi JS, Montgomery J, Brunt SJ, Nolan D, Price P. The immunological footprint of CMV in HIV-1 patients stable on long-term ART. Immun Ageing. 2015;12:14. PubMed PMID: 26435726. Pubmed Central PMCID: 4591633. doi: 10.1186/s12979-015-0041-0

20. Gianella S, Morris SR, Tatro E, Vargas MV, Haubrich RH, Daar ES, Dube MP, Richman DD, Little SJ, Smith DM. Virologic correlates of anti-CMV IgG levels in HIV-1-infected men. J Infect Dis. 2014;209(3):452-6. PubMed PMID: 23964106. Pubmed Central PMCID: 3883163. doi: 10.1093/infdis/jit434


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