Rosuvastatin Decreases Intestinal Fatty Acid Binding Protein (I-FABP), but does not Alter Zonulin or Lipopolysaccharide Binding Protein (LBP) Levels, in HIV-Infected Subjects on Antiretroviral Therapy
Article Sidebar
Main Article Content
Abstract
Introduction: Altered gastrointestinal (GI) barrier integrity and subsequent microbial translocation may contribute to immune activation in HIV infection. We have reported that rosuvastatin improved several markers of immune activation in HIV+ participants, but the effect of statin treatment on markers of GI barrier dysfunction is unknown.
Methods: SATURN-HIV is a randomized, double-blind, placebo-controlled trial assessing the effect of rosuvastatin (10mg/daily) on markers of cardiovascular disease, inflammation, and immune activation in ART-treated patients. Gut-barrier integrity was assessed by the surrogate markers intestinal fatty acid binding protein (I-FABP), a marker of enterocyte death, and zonulin-1, a marker of gut epithelial cell function. Levels of lipopolysaccharide binding protein (LBP) were measured as a marker of microbial translocation.
Results: Rosuvastatin significantly reduced levels of I-FABP during the treatment period compared to the placebo. There was no effect of rosuvastatin treatment on levels of zonulin or LBP. Baseline levels of LBP were directly related to several markers of immune activation in samples from all participants, including soluble CD163, IP-10, VCAM-1, TNFR-II, and the proportion of CD4+ and CD8+ T cells expressing CD38 and HLA-DR. Many of these relationships, however, were not seen in the statin arm alone at baseline or over time, as inflammatory markers often decreased and LBP levels were unchanged.
Conclusions: Forty-eight weeks of rosuvastatin treatment reduced levels of I-FABP, but did not affect levels of zonulin or LBP. The reduction in levels of inflammatory markers that we have reported with rosuvastatin treatment is likely mediated through other mechanisms not related to gut integrity or microbial translocation.
SATURN-HIV is registered on clinicaltrials.gov; Identifier: NCT01218802Downloads
Article Details
Pathogens and Immunity abides by Creative Commons BY 4.0:
http://creativecommons.org/licenses/by/4.0/
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
References
1. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol. 2013;119:51-83. PubMed PMID: 23886064. doi: 10.1016/B978-0-12-407707-2.00002-3
2. Funderburg NT. Markers of coagulation and inflammation often remain elevated in ART-treated HIV-infected patients. Curr Opin HIV AIDS. 2013. PubMed PMID: 24275673. doi: 10.1097/COH.0000000000000019
3. 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.
4. Emery S, Neuhaus JA, Phillips AN, Babiker A, Cohen CJ, Gatell JM, Girard PM, Grund B, Law M, Losso MH, Palfreeman A, Wood R. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197(8):1133-44. PubMed PMID: 18476292.
5. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4(12):977-87. PubMed PMID: 16341063. doi: 10.1038/nrd1901
6. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207. PubMed PMID: 18997196. doi: 10.1056/NEJMoa0807646
7. Eckard AR, Jiang Y, Debanne SM, Funderburg NT, McComsey GA. Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy. J Infect Dis. 2014;209(8):1156-64. PubMed PMID: 24415784. Pubmed Central PMCID: 3969551. doi: 10.1093/infdis/jiu012
8. Funderburg NT, Jiang Y, Debanne SM, Labbato D, Juchnowski S, Ferrari B, Clagett B, Robinson J, Lederman MM, McComsey GA. Rosuvastatin Reduces Vascular Inflammation and T-cell and Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2015;68(4):396-404. PubMed PMID: 25514794. Pubmed Central PMCID: 4334694. doi: 10.1097/QAI.0000000000000478
9. Funderburg NT, Jiang Y, Debanne SM, Storer N, Labbato D, Clagett B, Robinson J, Lederman MM, McComsey GA. Rosuvastatin Treatment Reduces Markers of Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy. Clin Infect Dis. 2014;58(4):588-95. PubMed PMID: 24253250. Pubmed Central PMCID: 3905756. doi: 10.1093/cid/cit748
10. Hatano H, Delwart EL, Norris PJ, Lee TH, Neilands TB, Kelley CF, Hunt PW, Hoh R, Linnen JM, Martin JN, Busch MP, Deeks SG. Evidence of persistent low-level viremia in long-term HAART-suppressed, HIV-infected individuals. AIDS. 2010;24(16):2535-9. PubMed PMID: 20651585. Pubmed Central PMCID: 2954261. doi: 10.1097/QAD.0b013e32833dba03
11. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, Tracy RP, Corey L, Deeks SG. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011;203(10):1474-83. PubMed PMID: 21502083. Pubmed Central PMCID: 3080892. doi: 10.1093/infdis/jir060
12. Piconi S, Parisotto S, Rizzardini G, Passerini S, Meraviglia P, Schiavini M, Niero F, Biasin M, Bonfanti P, Ricci ED, Trabattoni D, Clerici M. Atherosclerosis is associated with multiple pathogenic mechanisms in HIV-infected antiretroviral-naive or treated individuals. AIDS. 2013;27(3):381-9. PubMed PMID: 23079800. doi: 10.1097/QAD.0b013e32835abcc9
13. Zidar DA, Juchnowski S, Ferrari B, Clagett B, Pilch-Cooper HA, Rose S, Rodriguez B, McComsey GA, Sieg SF, Mehta NN, Lederman MM, Funderburg NT. Oxidized LDL levels are increased in HIV infection and may drive monocyte activation. J Acquir Immune Defic Syndr. 2015. PubMed PMID: 25647528. doi: 10.1097/QAI.0000000000000566
14. Klatt NR, Funderburg NT, Brenchley JM. Microbial translocation, immune activation, and HIV disease. Trends Microbiol. 2013;21(1):6-13. PubMed PMID: 23062765. Pubmed Central PMCID: 3534808. doi: 10.1016/j.tim.2012.09.001
15. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006. PubMed PMID: 17115046.
16. Funderburg NT, Andrade A, Chan ES, Rosenkranz SL, Lu D, Clagett B, Pilch-Cooper HA, Rodriguez B, Feinberg J, Daar E, Mellors J, Kuritzkes D, Jacobson JM, Lederman MM. Dynamics of immune reconstitution and activation markers in HIV+ treatment-naive patients treated with raltegravir, tenofovir disoproxil fumarate and emtricitabine. PLoS One. 2013;8(12):e83514. PubMed PMID: 24367599. Pubmed Central PMCID: 3867440. doi: 10.1371/journal.pone.0083514
17. Funderburg NT, Zidar DA, Shive C, Lioi A, Mudd J, Musselwhite LW, Simon DI, Costa MA, Rodriguez B, Sieg SF, Lederman MM. Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndromes. Blood. 2012. PubMed PMID: 23065151. doi: 10.1182/blood-2012-05-433946
18. Pandrea I, Cornell E, Wilson C, Ribeiro RM, Ma D, Kristoff J, Xu C, Haret-Richter GS, Trichel A, Apetrei C, Landay A, Tracy R. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood. 2012;120(7):1357-66. PubMed PMID: 22653975. Pubmed Central PMCID: 3423778. doi: 10.1182/blood-2012-03-414706
19. 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: 4192038. doi: 10.1093/infdis/jiu238
20. 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
21. Fasano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol. 2012;10(10):1096-100. PubMed PMID: 22902773. Pubmed Central PMCID: PMC3458511. doi: 10.1016/j.cgh.2012.08.012
22. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42(1):121-30. PubMed PMID: 3719049.
23. Longenecker CT, Hileman CO, Funderburg NT, McComsey GA. Rosuvastatin preserves renal function and lowers cystatin C in HIV-infected subjects on antiretroviral therapy: the SATURN-HIV trial. Clin Infect Dis. 2014;59(8):1148-56. PubMed PMID: 25015912. Pubmed Central PMCID: 4271099. doi: 10.1093/cid/ciu523
24. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187(10):1534-43. PubMed PMID: 12721933. doi: 10.1086/374786
25. Steele AK, Lee EJ, Vestal B, Hecht D, Dong Z, Rapaport E, Koeppe J, Campbell TB, Wilson CC. Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature. PLoS One. 2014;9(5):e97171. PubMed PMID: 24819230. Pubmed Central PMCID: PMC4018269. doi: 10.1371/journal.pone.0097171
26. Vanuytsel T, Vermeire S, Cleynen I. The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. Tissue Barriers. 2013;1(5):e27321. PubMed PMID: 24868498. Pubmed Central PMCID: PMC3943850. doi: 10.4161/tisb.27321
27. Gutsmann T, Muller M, Carroll SF, MacKenzie RC, Wiese A, Seydel U. Dual role of lipopolysaccharide (LPS)-binding protein in neutralization of LPS and enhancement of LPS-induced activation of mononuclear cells. Infect Immun. 2001;69(11):6942-50. PubMed PMID: 11598069. Pubmed Central PMCID: PMC100074. doi: 10.1128/IAI.69.11.6942-6950.2001
28. Nystrom J, Stenkvist J, Haggblom A, Weiland O, Nowak P. Low levels of microbial translocation marker LBP are associated with sustained viral response after anti-HCV treatment in HIV-1/HCV co-infected patients. PLoS One. 2015;10(3):e0118643. PubMed PMID: 25785448. Pubmed Central PMCID: PMC4364767. doi: 10.1371/journal.pone.0118643
29. Hileman CO, Turner R, N TF, Semba RD, McComsey GA. Changes in oxidized lipids drive the improvement in monocyte activation and vascular disease after statin therapy in HIV. AIDS. 2016;30(1):65-73. PubMed PMID: 26731754. doi: 10.1097/QAD.0000000000000885
30. Sandler NG, Douek DC. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol. 2012;10(9):655-66. PubMed PMID: 22886237. doi: 10.1038/nrmicro2848
31. Chung CY, Alden SL, Funderburg NT, Fu P, Levine AD. Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog. 2014;10(6):e1004198. PubMed PMID: 24968145. Pubmed Central PMCID: PMC4072797. doi: 10.1371/journal.ppat.1004198
32. Obinna FC, Cook G, Beale T, Dave S, Cunningham D, Fleming SC, Claydon E, Harris JW, Kapembwa MS. Comparative assessment of small intestinal and colonic permeability in HIV-infected homosexual men. AIDS. 1995;9(9):1009-16. PubMed PMID: 8527072.