Prospective Analysis of Lipid Composition Changes with Antiretroviral Therapy and Immune Activation in Persons Living with HIV

Main Article Content

Martha A. Belury
Emily Bowman
Janelle Gabriel
Brandon Snyder
Manjusha Kulkarni
Marilly Palettas
Xiaokui Mo
Jordan E. Lake
David Zidar
Scott F. Sieg
Benigno Rodriguez
Martin P. Playford
Adriana Andrade
Daniel R. Kuritzkes
Nehal N. Mehta
Michael M. Lederman
Nicholas Funderburg

Abstract

Background: Lipid profiles are altered by HIV infection and antiretroviral therapy (ART). Among HIV-uninfected (HIV-) populations the concentrations of various lipid classes (ie, lysophosphatidylcholine, LPC) and their saturated (SaFA), monounsaturated (MUFA), and polyunsaturated fatty acid (PUFA) composition are related to cardiometabolic disease risk. Associations between changes in the lipidome and immune activation in HIV-infected (HIV+) individuals beginning ART have not been described.

Methods: Plasma lipid concentrations and their fatty acid composition were measured by differential mobility spectroscopy in samples from 35 treatment-naive HIV+ participants beginning raltegravir (RAL)-based ART and from HIV- individuals (N=13) matched for age and sex.

Results: The levels of SaFA, including palmitic (16:0) and stearic (18:0) acid were enriched in HIV+ participants (pre- and post-ART), and SaFA levels were often positively correlated with levels of immune activation (ie, IL-6, sCD14, and TNFR1) at baseline and week 48. Levels of PUFAs (including 18:3, 20:4, and 20:5) were lower in HIV+ participants at baseline compared to levels in HIV- participants (P<0.01), and levels of these PUFAs were increased following 48 weeks of ART. Levels of PUFAs were often inversely related to immune activation. Levels of LPC were increased in HIV+ participants, both pre- and post-ART vs HIV- participants, and the composition of LPC was enriched for SaFAs among HIV+ individuals. At week 48, several LPC molecules containing SaFAs were positively correlated with levels of sCD14, D-dimer, and TNFR1 (P<0.01), and levels of PUFA-containing LPC (18:3, 20:5, 22:5, 22:6) were positively correlated with CD4+ T cell counts and inversely correlated with sCD14 and IL-6 (P<0.01).

Conclusions: The composition of the lipidome is altered in HIV infection and changes when ART is administered. Alterations in SaFAs were generally associated with inflammatory markers and may contribute to comorbid disease pathogenesis.

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Author Biography

Nicholas Funderburg, Ohio State University

Assistant Professor
School of Health and Rehabilitation Sciences
Division of Medical Laboratory Science

References

1. Funderburg NT, Mehta NN. Lipid Abnormalities and Inflammation in HIV Inflection. Curr HIV/AIDS Rep. 2016;13(4):218-25. PubMed PMID: 27245605. Pubmed Central PMCID: PMC4977198. doi: 10.1007/s11904-016-0321-0

2. Lake JE, Currier JS. Metabolic disease in HIV infection. Lancet Infect Dis. 2013;13(11):964-75. PubMed PMID: 24156897. doi: 10.1016/S1473-3099(13)70271-8

3. Munger AM, Chow DC, Playford MP, Parikh NI, Gangcuangco LM, Nakamoto BK, Kallianpur KJ, Ndhlovu LC, Shikuma CM, Mehta NN. Characterization of Lipid Composition and High-Density Lipoprotein Function in HIV-Infected Individuals on Stable Antiretroviral Regimens. AIDS Res Hum Retroviruses. 2015;31(2):221-8. PubMed PMID: 25416403. Pubmed Central PMCID: 4313425. doi: 10.1089/AID.2014.0239

4. Martinelli N, Girelli D, Malerba G, Guarini P, Illig T, Trabetti E, Sandri M, Friso S, Pizzolo F, Schaeffer L, Heinrich J, Pignatti PF, Corrocher R, Olivieri O. FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J Clin Nutr. 2008;88(4):941-9. PubMed PMID: 18842780.

5. Ueeda M, Doumei T, Takaya Y, Shinohata R, Katayama Y, Ohnishi N, Takaishi A, Miyoshi T, Hirohata S, Kusachi S. Serum N-3 polyunsaturated fatty acid levels correlate with the extent of coronary plaques and calcifications in patients with acute myocardial infarction. Circ J. 2008;72(11):1836-43. PubMed PMID: 18812674.

6. de Almeida IT, Cortez-Pinto H, Fidalgo G, Rodrigues D, Camilo ME. Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis. Clin Nutr. 2002;21(3):219-23. PubMed PMID: 12127930.

7. Hodge AM, English DR, O'Dea K, Sinclair AJ, Makrides M, Gibson RA, Giles GG. Plasma phospholipid and dietary fatty acids as predictors of type 2 diabetes: interpreting the role of linoleic acid. Am J Clin Nutr. 2007;86(1):189-97. PubMed PMID: 17616780.

8. Sun Q, Ma J, Campos H, Rexrode KM, Albert CM, Mozaffarian D, Hu FB. Blood concentrations of individual long-chain n-3 fatty acids and risk of nonfatal myocardial infarction. Am J Clin Nutr. 2008;88(1):216-23. PubMed PMID: 18614744.

9. Sacks FM, Lichtenstein AH, Wu JHY, Appel LJ, Creager MA, Kris-Etherton PM, Miller M, Rimm EB, Rudel LL, Robinson JG, Stone NJ, Van Horn LV, American Heart A. Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association. Circulation. 2017. PubMed PMID: 28620111. doi: 10.1161/CIR.0000000000000510

10. Robblee MM, Kim CC, Porter Abate J, Valdearcos M, Sandlund KL, Shenoy MK, Volmer R, Iwawaki T, Koliwad SK. Saturated Fatty Acids Engage an IRE1alpha-Dependent Pathway to Activate the NLRP3 Inflammasome in Myeloid Cells. Cell Rep. 2016;14(11):2611-23. PubMed PMID: 26971994. doi: 10.1016/j.celrep.2016.02.053

11. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol. 2007;27(1):84-91. PubMed PMID: 17082484. doi: 10.1161/01.ATV.0000251608.09329.9a

12. Reissig D, Rassoul F, Salvetter J, Wagner O, Richter V. Effect of fatty acids on expression of endothelial leukocyte adhesion molecules. Eur J Nutr. 2003;42(4):224-7. PubMed PMID: 12923654. doi: 10.1007/s00394-003-0408-4

13. Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, Guarda G, Tian Z, Tschopp J, Zhou R. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. 2013;38(6):1154-63. PubMed PMID: 23809162. doi: 10.1016/j.immuni.2013.05.015

14. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142(5):687-98. PubMed PMID: 20813258. Pubmed Central PMCID: PMC2956412. doi: 10.1016/j.cell.2010.07.041

15. Yamada H, Yoshida M, Nakano Y, Suganami T, Satoh N, Mita T, Azuma K, Itoh M, Yamamoto Y, Kamei Y, Horie M, Watada H, Ogawa Y. In vivo and in vitro inhibition of monocyte adhesion to endothelial cells and endothelial adhesion molecules by eicosapentaenoic acid. Arterioscler Thromb Vasc Biol. 2008;28(12):2173-9. PubMed PMID: 18948636. doi: 10.1161/ATVBAHA.108.171736

16. Wells IC, Peitzmeier G, Vincent JK. Lecithin: cholesterol acyltransferase and lysolecithin in coronary atherosclerosis. Exp Mol Pathol. 1986;45(3):303-10. PubMed PMID: 3466803.

17. Akerele OA, Cheema SK. Fatty acyl composition of lysophosphatidylcholine is important in atherosclerosis. Med Hypotheses. 2015. PubMed PMID: 26604024. doi: 10.1016/j.mehy.2015.10.013

18. Sasagawa T, Suzuki K, Shiota T, Kondo T, Okita M. The significance of plasma lysophospholipids in patients with renal failure on hemodialysis. J Nutr Sci Vitaminol (Tokyo). 1998;44(6):809-18. PubMed PMID: 10197312.

19. Rabini RA, Galassi R, Fumelli P, Dousset N, Solera ML, Valdiguie P, Curatola G, Ferretti G, Taus M, Mazzanti L. Reduced Na(+)-K(+)-ATPase activity and plasma lysophosphatidylcholine concentrations in diabetic patients. Diabetes. 1994;43(7):915-9. PubMed PMID: 8013757.

20. Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015;15(2):104-16. PubMed PMID: 25614320. doi: 10.1038/nri3793

21. Wu R, Huang YH, Elinder LS, Frostegard J. Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL. Arterioscler Thromb Vasc Biol. 1998;18(4):626-30. PubMed PMID: 9555869.

22. Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, Stuart LM, Latz E, Fitzgerald KA, Moore KJ. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14(8):812-20. PubMed PMID: 23812099. Pubmed Central PMCID: 3720827. doi: 10.1038/ni.2639

23. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11(2):155-61. PubMed PMID: 20037584. Pubmed Central PMCID: 2809046. doi: 10.1038/ni.1836

24. 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

25. 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

26. Nou E, Lu MT, Looby SE, Fitch KV, Kim EA, Lee H, Hoffmann U, Grinspoon SK, Lo J. Serum oxidized low-density lipoprotein decreases in response to statin therapy and relates independently to reductions in coronary plaque in patients with HIV. Aids. 2016;30(4):583-90. PubMed PMID: 26558731. doi: 10.1097/QAD.0000000000000946

27. Andrade A, Rosenkranz SL, Cillo AR, Lu D, Daar ES, Jacobson JM, Lederman M, Acosta EP, Campbell T, Feinberg J, Flexner C, Mellors JW, Kuritzkes DR, Team ACTGA. Three distinct phases of HIV-1 RNA decay in treatment-naive patients receiving raltegravir-based antiretroviral therapy: ACTG A5248. J Infect Dis. 2013;208(6):884-91. PubMed PMID: 23801609. Pubmed Central PMCID: 3749011. doi: 10.1093/infdis/jit272

28. 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

29. Funderburg NT, Xu D, Playford MP, Joshi AA, Andrade A, Kuritzkes DR, Lederman MM, Mehta NN. Treatment of HIV infection with a raltegravir-based regimen increases LDL levels, but improves HDL cholesterol efflux capacity. Antivir Ther. 2016. PubMed PMID: 27740536. doi: 10.3851/IMP3091

30. McCausland MR, Juchnowski SM, Zidar DA, Kuritzkes DR, Andrade A, Sieg SF, Lederman MM, Funderburg NT. Altered Monocyte Phenotype in HIV-1 Infection Tends to Normalize with Integrase-Inhibitor-Based Antiretroviral Therapy. PLoS One. 2015;10(10):e0139474. PubMed PMID: 26430882. Pubmed Central PMCID: PMC4591977. doi: 10.1371/journal.pone.0139474

31. Shalaurova I, Connelly MA, Garvey WT, Otvos JD. Lipoprotein insulin resistance index: a lipoprotein particle-derived measure of insulin resistance. Metab Syndr Relat Disord. 2014;12(8):422-9. PubMed PMID: 24959989. Pubmed Central PMCID: PMC4175429. doi: 10.1089/met.2014.0050

32. Dugani SB, Akinkuolie AO, Paynter N, Glynn RJ, Ridker PM, Mora S. Association of Lipoproteins, Insulin Resistance, and Rosuvastatin With Incident Type 2 Diabetes Mellitus : Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2016;1(2):136-45. PubMed PMID: 27347563. Pubmed Central PMCID: PMC4918085. doi: 10.1001/jamacardio.2016.0096

33. Bach G, Perrin-Cocon L, Gerossier E, Guironnet-Paquet A, Lotteau V, Inchauspe G, Fournillier A. Single lysophosphatidylcholine components exhibit adjuvant activities in vitro and in vivo. Clin Vaccine Immunol. 2010;17(3):429-38. PubMed PMID: 20071492. Pubmed Central PMCID: PMC2837973. doi: 10.1128/CVI.00420-09

34. Takahashi M, Okazaki H, Ogata Y, Takeuchi K, Ikeda U, Shimada K. Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen-activated protein kinase-dependent mechanism. Atherosclerosis. 2002;161(2):387-94. PubMed PMID: 11888522

35. Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol. 2005;25(10):2062-8. PubMed PMID: 16123319. doi: 10.1161/01.ATV.0000183883.72263.13

36. 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

37. Meikle PJ, Wong G, Tsorotes D, Barlow CK, Weir JM, Christopher MJ, MacIntosh GL, Goudey B, Stern L, Kowalczyk A, Haviv I, White AJ, Dart AM, Duffy SJ, Jennings GL, Kingwell BA. Plasma lipidomic analysis of stable and unstable coronary artery disease. Arterioscler Thromb Vasc Biol. 2011;31(11):2723-32. PubMed PMID: 21903946. doi: 10.1161/ATVBAHA.111.234096

38. Aiyar N, Disa J, Ao Z, Ju H, Nerurkar S, Willette RN, Macphee CH, Johns DG, Douglas SA. Lysophosphatidylcholine induces inflammatory activation of human coronary artery smooth muscle cells. Mol Cell Biochem. 2007;295(1-2):113-20. PubMed PMID: 16896535. doi: 10.1007/s11010-006-9280-x

39. 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

40. Kalayjian RC, Machekano RN, Rizk N, Robbins GK, Gandhi RT, Rodriguez BA, Pollard RB, Lederman MM, Landay A. Pretreatment levels of soluble cellular receptors and interleukin-6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy. J Infect Dis. 2010;201(12):1796-805. PubMed PMID: 20446847. Pubmed Central PMCID: 2873127. doi: 10.1086/652750

41. 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.

42. 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

43. Ross AC, Rizk N, O'Riordan MA, Dogra V, El-Bejjani D, Storer N, Harrill D, Tungsiripat M, Adell J, McComsey GA. Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis. 2009;49(7):1119-27. PubMed PMID: 19712036.

44. Kulkarni MB, E; Gabriel, J; Amburgy, T; Mayne, E; Zidar D; Maierhofer, C; Norris Turner, A; Bazan, J; Koletar, S; Lederman, M; Sieg, S; Funderburg,N. Altered Monocyte and Endothelial Cell Adhesion Molecule Expression is linked to Vascular Inflammation in HIV-infection Open Forum Infectious Diseases. 2016. doi: 10.1093/ofid/ofw224

45. Maisa A, Hearps AC, Angelovich TA, Pereira CF, Zhou J, Shi MD, Palmer CS, Muller WA, Crowe SM, Jaworowski A. Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. Aids. 2015;29(12):1445-57. PubMed PMID: 26244384. doi: 10.1097/QAD.0000000000000739

46. Westhorpe CL, Dufour EM, Maisa A, Jaworowski A, Crowe SM, Muller WA. Endothelial cell activation promotes foam cell formation by monocytes following transendothelial migration in an in vitro model. Exp Mol Pathol. 2012;93(2):220-6. PubMed PMID: 22609311. Pubmed Central PMCID: 3408785. S0014-4800(12)00078-0 [pii]. doi: 10.1016/j.yexmp.2012.03.014

47. Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, Rosenberg ES, Williams KC, Grinspoon S. 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(8):1227-36. PubMed PMID: 21917896. Pubmed Central PMCID: 3203384. doi: 10.1093/infdis/jir520

48. Willig AL, Overton ET. Metabolic Consequences of HIV: Pathogenic Insights. Curr HIV/AIDS Rep. 2014. PubMed PMID: 24390642. doi: 10.1007/s11904-013-0191-7

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