A Randomized Controlled Trial of Lisinopril to Decrease Lymphoid Fibrosis in Antiretroviral-Treated, HIV-infected Individuals

Leslie Renee Cockerham, Steven A. Yukl, Kara Harvill, Ma Somsouk, Sunil K. Joshi, Elizabeth Sinclair, Teri Liegler, Rebecca Hoh, Sophie Lyons, Peter W. Hunt, Adam Rupert, Irini Sereti, David R. Morcock, Ajantha Rhodes, Claire Emson, Marc K. Hellerstein, Jacob D. Estes, Sharon Lewin, Steven G. Deeks, Hiroyu Hatano

Abstract


Background: In HIV infection, lymphoid tissue is disrupted by fibrosis. Angiotensin converting enzyme inhibitors have anti-fibrotic properties. We completed a pilot study to assess whether the addition of lisinopril to antiretroviral therapy (ART) reverses fibrosis of gut tissue, and whether this leads to reduction of HIV RNA and DNA levels.

Methods: Thirty HIV-infected individuals on ART were randomized to lisinopril at 20mg daily or matching placebo for 24 weeks. All participants underwent rectal biopsies prior to starting the study drug and at 22 weeks, and there were regular blood draws. The primary end point was the change in HIV RNA and DNA levels in rectal tissue. Secondary outcomes included the change in 1) HIV levels in blood; 2) Gag-specific T-cell responses; 3) levels of T-cell activation; and 4) collagen deposition.

Results: The addition of lisinopril did not have a significant effect on the levels of HIV RNA or DNA in gut tissue or blood, Gag-specific responses, or levels of T-cell activation. Lisinopril also did not have a significant impact on lymphoid fibrosis in the rectum, as assessed by quantitative histology or heavy water labeling.

Conclusions: Treatment with lisinopril for 24 weeks in HIV-infected adults did not have an effect on lymphoid fibrosis, immune activation, or gut tissue viral reservoirs. Further study is needed to see if other anti-fibrotic agents may be useful in reversing lymphoid fibrosis and reducing HIV levels.

Clinical Trials Registration: NCT01535235


Keywords


Anti-Inflammatory Agents/therapeutic use; CD4 Lymphocyte Count; Disease Reservoirs/*virology; HIV; Immunology; Lymphoid fibrosis;T-cell activation

Full Text:

HTML PDF

References


1. Schacker TW, Nguyen PL, Beilman GJ, Wolinsky S, Larson M, Reilly C, Haase AT. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest. 2002;110(8):1133-9. PubMed PMID: 12393849. Pubmed Central PMCID: PMC150803. doi: 10.1172/JCI16413

2. Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity. 2006;25(6):989-1001. PubMed PMID: 17112751. Pubmed Central PMCID: PMC2692293. doi: 10.1016/j.immuni.2006.10.011

3. Zeng M, Smith AJ, Wietgrefe SW, Southern PJ, Schacker TW, Reilly CS, Estes JD, Burton GF, Silvestri G, Lifson JD, Carlis JV, Haase AT. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest. 2011;121(3):998-1008. PubMed PMID: 21393864. Pubmed Central PMCID: 3049394. doi: 10.1172/jci45157

4. Zeng M, Paiardini M, Engram JC, Beilman GJ, Chipman JG, Schacker TW, Silvestri G, Haase AT. Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution. Blood. 2012;120(9):1856-67. PubMed PMID: 22613799. Pubmed Central PMCID: 3433090. doi: 10.1182/blood-2012-03-418624

5. Schacker TW, Nguyen PL, Martinez E, Reilly C, Gatell JM, Horban A, Bakowska E, Berzins B, van Leeuwen R, Wolinsky S, Haase AT, Murphy RL. Persistent abnormalities in lymphoid tissues of human immunodeficiency virus-infected patients successfully treated with highly active antiretroviral therapy. J Infect Dis. 2002;186(8):1092-7. PubMed PMID: 12355359. doi: 10.1086/343802

6. Sanchez JL, Hunt PW, Reilly CS, Hatano H, Beilman GJ, Khoruts A, Jasurda JS, Somsouk M, Thorkelson A, Russ S, Anderson J, Deeks SG, Schacker TW. Lymphoid fibrosis occurs in long-term nonprogressors and persists with antiretroviral therapy, but may be reversible with curative interventions. J Infect Dis. 2014. PubMed PMID: 25344521. doi: 10.1093/infdis/jiu586

7. Diaz A, Alos L, Leon A, Mozos A, Caballero M, Martinez A, Plana M, Gallart T, Gil C, Leal M, Gatell JM, Garcia F, Study Group of Lymphoid Tissue immunopathogenesis in HIVi. Factors associated with collagen deposition in lymphoid tissue in long-term treated HIV-infected patients. AIDS. 2010;24(13):2029-39. PubMed PMID: 20588162. doi: 10.1097/QAD.0b013e32833c3268

8. Estes J, Baker JV, Brenchley JM, Khoruts A, Barthold JL, Bantle A, Reilly CS, Beilman GJ, George ME, Douek DC, Haase AT, Schacker TW. Collagen deposition limits immune reconstitution in the gut. J Infect Dis. 2008;198(4):456-64. PubMed PMID: 18598193. Pubmed Central PMCID: 2683984. doi: 10.1086/590112

9. Schacker TW, Reilly C, Beilman GJ, Taylor J, Skarda D, Krason D, Larson M, Haase AT. Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 cell count. AIDS. 2005;19(18):2169-71. PubMed PMID: 16284469.

10. Asmuth DM, Pinchuk IV, Wu J, Vargas G, Chen X, Mann S, Albanese A, Ma ZM, Saroufeem R, Melcher GP, Troia-Cancio P, Torok NJ, Miller CJ, Powell DW. Role of intestinal myofibroblasts in HIV-associated intestinal collagen deposition and immune reconstitution following combination antiretroviral therapy. AIDS. 2015;29(8):877-88. PubMed PMID: 25784439. doi: 10.1097/QAD.0000000000000636

11. Donovan GM, Lythe G. T cell and reticular network co-dependence in HIV infection. J Theor Biol. 2016;395:211-20. PubMed PMID: 26874227. doi: 10.1016/j.jtbi.2016.01.040

12. Estes JD, Wietgrefe S, Schacker T, Southern P, Beilman G, Reilly C, Milush JM, Lifson JD, Sodora DL, Carlis JV, Haase AT. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection. J Infect Dis. 2007;195(4):551-61. PubMed PMID: 17230415. doi: 10.1086/510852

13. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med. 1994;331(19):1286-92. PubMed PMID: 7935686. doi: 10.1056/NEJM199411103311907

14. Hunt PW, Hatano H, Somsouk M, Sinclair E, ., Epling L, Gilman L, Martin J, Deeks S, Schacker T. Gut-associated Lymphoid Tissue Fibrosis Is Associated with CD4+ T Cell Activation and Poor HIV-specific CD8+ T Cell Responses during Suppressive ART [abstract 319]. 18th Conference on Retroviruses and Opportunistic Infections; Boston2011.

15. Laurent GJ. Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. Am J Physiol. 1987;252(1 Pt 1):C1-9. PubMed PMID: 3544859.

16. Molteni A, Wolfe LF, Ward WF, Ts'ao CH, Molteni LB, Veno P, Fish BL, Taylor JM, Quintanilla N, Herndon B, Moulder JE. Effect of an angiotensin II receptor blocker and two angiotensin converting enzyme inhibitors on transforming growth factor-beta (TGF-beta) and alpha-actomyosin (alpha SMA), important mediators of radiation-induced pneumopathy and lung fibrosis. Curr Pharm Des. 2007;13(13):1307-16. PubMed PMID: 17506716.

17. Gross O, Schulze-Lohoff E, Koepke ML, Beirowski B, Addicks K, Bloch W, Smyth N, Weber M. Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis. Nephrol Dial Transplant. 2004;19(7):1716-23. PubMed PMID: 15128880. doi: 10.1093/ndt/gfh219

18. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation. 2000;102(12):1388-93. PubMed PMID: 10993857.

19. Sharma K, Eltayeb BO, McGowan TA, Dunn SR, Alzahabi B, Rohde R, Ziyadeh FN, Lewis EJ. Captopril-induced reduction of serum levels of transforming growth factor-beta1 correlates with long-term renoprotection in insulin-dependent diabetic patients. Am J Kidney Dis. 1999;34(5):818-23. PubMed PMID: 10561136.

20. Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, Crane HM, Willig J, Mugavero M, Saag M, Martin JN, Deeks SG. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48(6):787-94. PubMed PMID: 19193107. Pubmed Central PMCID: 2720023. doi: 10.1086/597093

21. Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, Choi AL, Girling V, Ho T, Li P, Fujimoto K, Lampiris H, Hare CB, Pandori M, Haase AT, Gunthard HF, Fischer M, Shergill AK, McQuaid K, Havlir DV, Wong JK. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis. 2010;202(10):1553-61. PubMed PMID: 20939732. Pubmed Central PMCID: 2997806. doi: 10.1086/656722

22. Yukl SA, Shergill AK, Ho T, Killian M, Girling V, Epling L, Li P, Wong LK, Crouch P, Deeks SG, Havlir DV, McQuaid K, Sinclair E, Wong JK. The Distribution of HIV DNA and RNA in Cell Subsets Differs in Gut and Blood of HIV-Positive Patients on ART: Implications for Viral Persistence. J Infect Dis. 2013. PubMed PMID: 23852128. doi: 10.1093/infdis/jit308

23. Yukl SA, Kaiser P, Kim P, Li P, Wong JK. Advantages of using the QIAshredder instead of restriction digestion to prepare DNA for droplet digital PCR. Biotechniques. 2014;56(4):194-6. PubMed PMID: 24724845. doi: 10.2144/000114159

24. Kaiser P, Niederost B, Joos B, von Wyl V, Opravil M, Weber R, Gunthard HF, Fischer M. Equal amounts of intracellular and virion-enclosed hepatitis C virus RNA are associated with peripheral-blood mononuclear cells in vivo. J Infect Dis. 2006;194(12):1713-23. PubMed PMID: 17109344. doi: 10.1086/508431

25. Pasternak AO, Jurriaans S, Bakker M, Prins JM, Berkhout B, Lukashov VV. Cellular levels of HIV unspliced RNA from patients on combination antiretroviral therapy with undetectable plasma viremia predict the therapy outcome. PLoS One. 2009;4(12):e8490. PubMed PMID: 20046870. Pubmed Central PMCID: 2795168. doi: 10.1371/journal.pone.0008490

26. Lewin SR, Vesanen M, Kostrikis L, Hurley A, Duran M, Zhang L, Ho DD, Markowitz M. Use of real-time PCR and molecular beacons to detect virus replication in human immunodeficiency virus type 1-infected individuals on prolonged effective antiretroviral therapy. J Virol. 1999;73(7):6099-103. PubMed PMID: 10364365. Pubmed Central PMCID: 112674.

27. Lewin SR, Murray JM, Solomon A, Wightman F, Cameron PU, Purcell DJ, Zaunders JJ, Grey P, Bloch M, Smith D, Cooper DA, Kelleher AD. Virologic determinants of success after structured treatment interruptions of antiretrovirals in acute HIV-1 infection. J Acquir Immune Defic Syndr. 2008;47(2):140-47. PubMed PMID: 18300365.

28. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Xue X, Hunt P, Karim R, Kern DM, Hodis HN, Deeks SG. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis. 2011;203(4):452-63. PubMed PMID: 21220772. Pubmed Central PMCID: 3071219. doi: 10.1093/infdis/jiq071

29. Hatano H, Yukl SA, Ferre AL, Graf EH, Somsouk M, Sinclair E, Abdel-Mohsen M, Liegler T, Harvill K, Hoh R, Palmer S, Bacchetti P, Hunt PW, Martin JN, McCune JM, Tracy RP, Busch MP, O'Doherty U, Shacklett BL, Wong JK, Deeks SG. Prospective Antiretroviral Treatment of Asymptomatic, HIV-1 Infected Controllers. PLoS Pathog. 2013;9(10):e1003691. PubMed PMID: 24130489. Pubmed Central PMCID: 3795031. doi: 10.1371/journal.ppat.1003691

30. Ndhlovu LC, Sinclair E, Epling L, Tan QX, Ho T, Jha AR, Eccles-James I, Tincati C, Levy JA, Nixon DF, Hecht FM, Barbour JD. IL-2 immunotherapy to recently HIV-1 infected adults maintains the numbers of IL-17 expressing CD4+ T (T(H)17) cells in the periphery. J Clin Immunol. 2010;30(5):681-92. PubMed PMID: 20571894. Pubmed Central PMCID: 2935971. doi: 10.1007/s10875-010-9432-3

31. Ferre AL, Hunt PW, Critchfield JW, Young DH, Morris MM, Garcia JC, Pollard RB, Yee HF, Jr., Martin JN, Deeks SG, Shacklett BL. Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood. 2009;113(17):3978-89. PubMed PMID: 19109229. Pubmed Central PMCID: 2673124. doi: 10.1182/blood-2008-10-182709

32. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203. PubMed PMID: 18942885. Pubmed Central PMCID: 2570418. doi: 10.1371/journal.pmed.0050203

33. 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: 3071127. doi: 10.1093/infdis/jiq118

34. Rodger AJ, Fox Z, Lundgren JD, Kuller LH, Boesecke C, Gey D, Skoutelis A, Goetz MB, Phillips AN, Group ISfMoATS. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis. 2009;200(6):973-83. PubMed PMID: 19678756. Pubmed Central PMCID: PMC2892757. doi: 10.1086/605447

35. Boulware DR, Hullsiek KH, Puronen CE, Rupert A, Baker JV, French MA, Bohjanen PR, Novak RM, Neaton JD, Sereti I, Group IS. 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. J Infect Dis. 2011;203(11):1637-46. PubMed PMID: 21592994. Pubmed Central PMCID: PMC3096784. doi: 10.1093/infdis/jir134

36. Powell DW, Pinchuk IV, Saada JI, Chen X, Mifflin RC. Mesenchymal cells of the intestinal lamina propria. Annu Rev Physiol. 2011;73:213-37. PubMed PMID: 21054163. Pubmed Central PMCID: PMC3754809. doi: 10.1146/annurev.physiol.70.113006.100646

37. Deleage C, Schuetz A, Alvord WG, Johnston L, Hao XP, Morcock DR, Rerknimitr R, Fletcher JL, Puttamaswin S, Phanuphak N, Dewar R, McCune JM, Sereti I, Robb M, Kim JH, Schacker TW, Hunt P, Lifson JD, Ananworanich J, Estes JD. Impact of early cART in the gut during acute HIV infection. JCI Insight. 2016;1(10). PubMed PMID: 27446990. Pubmed Central PMCID: 4951101. doi: 10.1172/jci.insight.87065

38. Tabb B, Morcock DR, Trubey CM, Quinones OA, Hao XP, Smedley J, Macallister R, Piatak M, Jr., Harris LD, Paiardini M, Silvestri G, Brenchley JM, Alvord WG, Lifson JD, Estes JD. Reduced inflammation and lymphoid tissue immunopathology in rhesus macaques receiving anti-tumor necrosis factor treatment during primary simian immunodeficiency virus infection. J Infect Dis. 2013;207(6):880-92. PubMed PMID: 23087435. Pubmed Central PMCID: 3571439. doi: 10.1093/infdis/jis643

39. Decaris ML, Gatmaitan M, FlorCruz S, Luo F, Li K, Holmes WE, Hellerstein MK, Turner SM, Emson CL. Proteomic analysis of altered extracellular matrix turnover in bleomycin-induced pulmonary fibrosis. Mol Cell Proteomics. 2014;13(7):1741-52. PubMed PMID: 24741116. Pubmed Central PMCID: 4083112. doi: 10.1074/mcp.M113.037267

40. Decaris ML, Emson CL, Li K, Gatmaitan M, Luo F, Cattin J, Nakamura C, Holmes WE, Angel TE, Peters MG, Turner SM, Hellerstein MK. Turnover rates of hepatic collagen and circulating collagen-associated proteins in humans with chronic liver disease. PLoS One. 2015;10(4):e0123311. PubMed PMID: 25909381. Pubmed Central PMCID: 4409311. doi: 10.1371/journal.pone.0123311

41. Holmes WE, Angel TE, Li KW, Hellerstein MK. Dynamic Proteomics: In Vivo Proteome-Wide Measurement of Protein Kinetics Using Metabolic Labeling. Methods Enzymol. 2015;561:219-76. PubMed PMID: 26358907. doi: 10.1016/bs.mie.2015.05.018

42. Hunt PW, Shulman NS, Hayes TL, Dahl V, Somsouk M, Funderburg NT, McLaughlin B, Landay AL, Adeyemi O, Gilman LE, Clagett B, Rodriguez B, Martin JN, Schacker TW, Shacklett BL, Palmer S, Lederman MM, Deeks SG. The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial. Blood. 2013;121(23):4635-46. PubMed PMID: 23589670. doi: 10.1182/blood-2012-06-436345

43. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, Hsue P, Emu B, Krone M, Lampiris H, Douek D, Martin JN, Deeks SG. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197(1):126-33. PubMed PMID: 18171295. Pubmed Central PMCID: 3466592. doi: 10.1086/524143

44. Ahamed J, Terry H, Choi ME, Laurence J. Transforming Growth Factor-beta1-mediated cardiac fibrosis: Potential role in HIV and HIV/ART-linked cardiovascular disease. AIDS. 2015. PubMed PMID: 26605511. doi: 10.1097/QAD.0000000000000982

45. Estes JD, Reilly C, Trubey CM, Fletcher CV, Cory TJ, Piatak M, Jr., Russ S, Anderson J, Reimann TG, Star R, Smith A, Tracy RP, Berglund A, Schmidt T, Coalter V, Chertova E, Smedley J, Haase AT, Lifson JD, Schacker TW. Antifibrotic therapy in simian immunodeficiency virus infection preserves CD4+ T-cell populations and improves immune reconstitution with antiretroviral therapy. J Infect Dis. 2015;211(5):744-54. PubMed PMID: 25246534. Pubmed Central PMCID: PMC4334805. doi: 10.1093/infdis/jiu519

46. Fischer M, Joos B, Hirschel B, Bleiber G, Weber R, Gunthard HF, Swiss HIVCS. Cellular viral rebound after cessation of potent antiretroviral therapy predicted by levels of multiply spliced HIV-1 RNA encoding nef. J Infect Dis. 2004;190(11):1979-88. PubMed PMID: 15529263. doi: 10.1086/425983

47. Fischer M, Wong JK, Russenberger D, Joos B, Opravil M, Hirschel B, Trkola A, Kuster H, Weber R, Gunthard HF, Swiss HIVCS. Residual cell-associated unspliced HIV-1 RNA in peripheral blood of patients on potent antiretroviral therapy represents intracellular transcripts. Antivir Ther. 2002;7(2):91-103. PubMed PMID: 12212929.

48. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sekaly RP. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15(8):893-900. PubMed PMID: 19543283. Pubmed Central PMCID: 2859814. doi: 10.1038/nm.1972

49. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Xue X, Hunt P, Karim R, Kern DM, Hodis HN, Deeks SG. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis. 2011;203(4):452-63. PubMed PMID: 21220772. Pubmed Central PMCID: 3071219. doi: 10.1093/infdis/jiq071

50. Deleage C, Wietgrefe SW, Del Prete G, Morcock DR, Hao XP, Piatak M, Jr., Bess J, Anderson JL, Perkey KE, Reilly C, McCune JM, Haase AT, Lifson JD, Schacker TW, Estes JD. Defining HIV and SIV Reservoirs in Lymphoid Tissues. Pathog Immun. 2016;1(1):68-106. PubMed PMID: 27430032. Pubmed Central PMCID: 4943335.


Article Level Metrics

Refbacks

  • There are currently no refbacks.




Copyright (c) 2017 Leslie Renee Cockerham

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

© Pathogens and Immunity 2018

Case Western Reserve University; Division of Infectious Diseases

10900 Euclid Ave.; Mailstop 4984; Cleveland, OH 44106

(216) 368-6317; ISSN: 2469-2964; info@paijournal.com