Lack of Atorvastatin Effect on Monocyte Gene Expression and Inflammatory Markers in HIV-1- infected ART-suppressed Individuals at Risk of non-AIDS Comorbidities

Main Article Content

Anjana Yadav
Andrew V. Kossenkov
Louise C. Showe
Sarah J. Ratcliffe
Grace H. Choi
Luis J. Montaner
Pablo Tebas
Pamela A. Shaw
Ronald Collman


Background: Many people living with HIV have persistent monocyte activation despite viral suppression by antiretroviral therapy (ART), which contributes to non-AIDS complications including neurocognitive and other disorders. Statins have immunomodulatory properties that might be beneficial by reducing monocyte activation. 

Methods: We previously characterized monocyte gene expression and inflammatory markers in 11 HIV-positive individuals on long-term ART (HIV/ART) at risk for non-AIDS complications because of low nadir CD4+ counts (median 129 cells/uL) and elevated hsCRP. Here, these individuals participated in a double-blind, randomized, placebo-controlled crossover study of 12 weeks of atorvastatin treatment. Monocyte surface markers were assessed by flow cytometry, plasma mediators by ELISA and Luminex, and monocyte gene expression by microarray analysis. 

Results: Among primary outcome measures, 12 weeks of atorvastatin treatment led to an unexpected increase in CCR2+ monocytes (P=0.04), but did not affect CD16+ or CD163+ monocytes, nor levels in plasma of CCL2/MCP-1 or sCD14. Among secondary outcomes, atorvastatin treatment was associated with decreased plasma hsCRP (P=0.035) and IL-2R (P=0.012). Treatment was also associated with increased total CD14+ monocytes (P=0.015), and increased plasma CXCL9 (P=0.003) and IL-12 (P<0.001). Comparable results were seen in a subgroup that had inflammatory marker elevations at baseline. Atorvastatin treatment did not significantly alter monocyte gene expression or normalize aberrant baseline transcriptional patterns.

Conclusions: In this study of aviremic HIV+ individuals at high risk of non-AIDS events, 12 weeks of atorvastatin did not normalize monocyte gene expression patterns nor lead to significant changes in monocyte surface markers or plasma mediators linked to non-AIDS comorbidities. 


Download data is not yet available.

Article Details



Croxford S, Kitching A, Desai S, Kall M, Edelstein M, Skingsley A, Burns F, Copas A, Brown AE, Sullivan AK, Delpech V. Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: an analysis of a national observational cohort. Lancet Public Health. 2017;2(1):e35-e46. doi: 10.1016/S2468-2667(16)30020-2. PubMed PMID: 29249478.

Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, Alger J, Singer E, Campbell T, Yiannoutsos C, Cohen R, Navia B, Consortium HIVN. Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS. 2011;25(5):625-33. doi: 10.1097/QAD.0b013e3283427da7. PubMed PMID: 21297425; PMCID: PMC4326227.

Gannon P, Khan MZ, Kolson DL. Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol. 2011;24(3):275-83. doi: 10.1097/WCO.0b013e32834695fb. PubMed PMID: 21467932; PMCID: PMC3683661.

Williams DW, Eugenin EA, Calderon TM, Berman JW. Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol. 2012;91(3):401-15. doi: 10.1189/jlb.0811394. PubMed PMID: 22227964; PMCID: PMC3289493.

Sacktor N, Skolasky RL, Seaberg E, Munro C, Becker JT, Martin E, Ragin A, Levine A, Miller E. Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology. 2016;86(4):334-40. doi: 10.1212/WNL.0000000000002277. PubMed PMID: 26718568; PMCID: PMC4776086.

Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C, Group H. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17(1):3-16. doi: 10.1007/s13365-010-0006-1. PubMed PMID: 21174240; PMCID: PMC3032197.

Kamat A, Lyons JL, Misra V, Uno H, Morgello S, Singer EJ, Gabuzda D. Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr. 2012;60(3):234-43. doi: 10.1097/QAI.0b013e318256f3bc. PubMed PMID: 22569268; PMCID: PMC3383928.

Gonzalez E, Rovin BH, Sen L, Cooke G, Dhanda R, Mummidi S, Kulkarni H, Bamshad MJ, Telles V, Anderson SA, Walter EA, Stephan KT, Deucher M, Mangano A, Bologna R, Ahuja SS, Dolan MJ, Ahuja SK. HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci USA. 2002;99(21):13795-800. doi: 10.1073/pnas.202357499. PubMed PMID: 12374865; PMCID: PMC129777.

Scully E, Lockhart A, Huang L, Robles Y, Becerril C, Romero-Tejeda M, Albrecht MA, Palmer CD, Bosch RJ, Altfeld M, Kuritzkes DR, Lin NH. Elevated Levels of Microbial Translocation Markers and CCL2 Among Older HIV-1-Infected Men. J Infect Dis. 2016;213(5):771-5. doi: 10.1093/infdis/jiv501. PubMed PMID: 26494772; PMCID: PMC4747622.

Jumare J, Akolo C, Ndembi N, Bwala S, Alabi P, Okwuasaba K, Adebiyi R, Umlauf A, Cherner M, Abimiku A, Charurat M, Blattner WA, Royal W, 3rd. Elevated Plasma Levels of sCD14 and MCP-1 Are Associated With HIV Associated Neurocognitive Disorders Among Antiretroviral-Naive Individuals in Nigeria. J Acquir Immune Defic Syndr. 2020;84(2):196-202. doi: 10.1097/QAI.0000000000002320. PubMed PMID: 32084055.

Veenstra M, Leon-Rivera R, Li M, Gama L, Clements JE, Berman JW. Mechanisms of CNS Viral Seeding by HIV(+) CD14(+) CD16(+) Monocytes: Establishment and Reseeding of Viral Reservoirs Contributing to HIV-Associated Neurocognitive Disorders. mBio. 2017;8(5). doi: 10.1128/mBio.01280-17. PubMed PMID: 29066542; PMCID: PMC5654927.

Ndhlovu LC, Umaki T, Chew GM, Chow DC, Agsalda M, Kallianpur KJ, Paul R, Zhang G, Ho E, Hanks N, Nakamoto B, Shiramizu BT, Shikuma CM. Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND). J Neurovirol. 2014;20(6):571-82. doi: 10.1007/s13365-014-0279-x. PubMed PMID: 25227930; PMCID: PMC4268390.

Buckner CM, Calderon TM, Willams DW, Belbin TJ, Berman JW. Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood-brain barrier and infection by HIV: implications for NeuroAIDS. Cell Immunol. 2011;267(2):109-23. doi: 10.1016/j.cellimm.2010.12.004. PubMed PMID: 21292246; PMCID: PMC4335637.

Veenstra M, Byrd DA, Inglese M, Buyukturkoglu K, Williams DW, Fleysher L, Li M, Gama L, Leon-Rivera R, Calderon TM, Clements JE, Morgello S, Berman JW. CCR2 on Peripheral Blood CD14(+)CD16(+) Monocytes Correlates with Neuronal Damage, HIV-Associated Neurocognitive Disorders, and Peripheral HIV DNA: reseeding of CNS reservoirs? J Neuroimmune Pharmacol. 2019;14(1):120-33. doi: 10.1007/s11481-018-9792-7. PubMed PMID: 29981000; PMCID: PMC6320730.

Subramanya V, McKay HS, Brusca RM, Palella FJ, Kingsley LA, Witt MD, Hodis HN, Tracy RP, Post WS, Haberlen SA. Inflammatory biomarkers and subclinical carotid atherosclerosis in HIV-infected and HIV-uninfected men in the Multicenter AIDS Cohort Study. PLoS One. 2019;14(4):e0214735. doi: 10.1371/journal.pone.0214735. PubMed PMID: 30946765; PMCID: PMC6448851.

Alcaide ML, Parmigiani A, Pallikkuth S, Roach M, Freguja R, Della Negra M, Bolivar H, Fischl MA, Pahwa S. Immune activation in HIV-infected aging women on antiretrovirals—implications for age-associated comorbidities: a cross-sectional pilot study. PLoS One. 2013;8(5):e63804. doi: 10.1371/journal.pone.0063804. PubMed PMID: 23724003; PMCID: PMC3665816.

Paiardini M, Muller-Trutwin M. HIV-associated chronic immune activation. Immunol Rev. 2013;254(1):78-101. doi: 10.1111/imr.12079. PubMed PMID: 23772616; PMCID: PMC3729961.

Crum-Cianflone NF, Moore DJ, Letendre S, Poehlman Roediger M, Eberly L, Weintrob A, Ganesan A, Johnson E, Del Rosario R, Agan BK, Hale BR. Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons. Neurology. 2013;80(4):371-9. doi: 10.1212/WNL.0b013e31827f0776. PubMed PMID: 23303852; PMCID: PMC3589242.

McCutchan JA, Wu JW, Robertson K, Koletar SL, Ellis RJ, Cohn S, Taylor M, Woods S, Heaton R, Currier J, Williams PL. HIV suppression by HAART preserves cognitive function in advanced, immune-reconstituted AIDS patients. AIDS. 2007;21(9):1109-17. doi: 10.1097/QAD.0b013e3280ef6acd. PubMed PMID: 17502721.

Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. doi: 10.1146/annurev.pharmtox.45.120403.095748. PubMed PMID: 15822172; PMCID: PMC2694580.

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. doi: 10.1093/cid/cit748. PubMed PMID: 24253250; PMCID: PMC3905756.

Hileman CO, Turner R, Funderburg NT, 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. doi: 10.1097/QAD.0000000000000885. PubMed PMID: 26731754; PMCID: PMC4703362.

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. doi: 10.1097/QAI.0000000000000478. PubMed PMID: 25514794; PMCID: PMC4334694.

Yadav A, Betts MR, Collman RG. Statin modulation of monocyte phenotype and function: implications for HIV-1-associated neurocognitive disorders. J Neurovirol. 2016;22(5):584-96. doi: 10.1007/s13365-016-0433-8. PubMed PMID: 27021071; PMCID: PMC5040617.

Ehinger E, Ghosheh Y, Pramod AB, Lin J, Hanna DB, Mueller K, Durant CP, Baas L, Qi Q, Wang T, Buscher K, Anastos K, Lazar JM, Mack WJ, Tien PC, Cohen MH, Ofotokun I, Gange S, Heath SL, Hodis HN, Tracy RP, Landay AL, Kaplan RC, Ley K. Classical monocyte transcriptomes reveal significant anti-inflammatory statin effect in women with chronic HIV. Cardiovasc Res. 2021;117(4):1166-77. doi: 10.1093/cvr/cvaa188. PubMed PMID: 32658258; PMCID: PMC7983000.

Rice JB, Stoll LL, Li WG, Denning GM, Weydert J, Charipar E, Richenbacher WE, Miller FJ, Jr., Weintraub NL. Low-level endotoxin induces potent inflammatory activation of human blood vessels: inhibition by statins. Arterioscler Thromb Vasc Biol. 2003;23(9):1576-82. doi: 10.1161/01.ATV.0000081741.38087.F9. PubMed PMID: 12816876.

Li JJ, Chen XJ. Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide. Coron Artery Dis. 2003;14(4):329-34. doi: 10.1097/01.mca.0000078062.22445.60. PubMed PMID: 12826933.

Yadav A, Kossenkov AV, Knecht VR, Showe LC, Ratcliffe SJ, Montaner LJ, Tebas P, Collman RG. Evidence for Persistent Monocyte and Immune Dysregulation After Prolonged Viral Suppression Despite Normalization of Monocyte Subsets, sCD14 and sCD163 in HIV-Infected Individuals. Pathog Immun. 2019;4(2):324-62. doi: 10.20411/pai.v4i2.336. PubMed PMID: 31893252; PMCID: PMC6930814.

Zhang S. A comprehensive evaluation of SAM, the SAM R-package and a simple modification to improve its performance. BMC Bioinformatics. 2007;8:230. doi: 10.1186/1471-2105-8-230. PubMed PMID: 17603887; PMCID: PMC1955751.

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):267-73. doi: 10.1038/ng1180. PubMed PMID: 12808457.

Shive CL, Jiang W, Anthony DD, Lederman MM. Soluble CD14 is a nonspecific marker of monocyte activation. AIDS. 2015;29(10):1263-5. doi: 10.1097/QAD.0000000000000735. PubMed PMID: 26035325; PMCID: PMC4452959.

Sunil M, Nigalye M, Somasunderam A, Martinez ML, Yu X, Arduino RC, Utay NS, Bell TK. Unchanged Levels of Soluble CD14 and IL-6 Over Time Predict Serious Non-AIDS Events in HIV-1-Infected People. AIDS Res Hum Retroviruses. 2016;32(12):1205-9. doi: 10.1089/AID.2016.0007. PubMed PMID: 27344921; PMCID: PMC5175436.

Williams DW, Calderon TM, Lopez L, Carvallo-Torres L, Gaskill PJ, Eugenin EA, Morgello S, Berman JW. Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis. PLoS One. 2013;8(7):e69270. doi: 10.1371/journal.pone.0069270. PubMed PMID: 23922698; PMCID: PMC3724935.

Carmona S, Bor J, Nattey C, Maughan-Brown B, Maskew M, Fox MP, Glencross DK, Ford N, MacLeod WB. Persistent High Burden of Advanced HIV Disease Among Patients Seeking Care in South Africa’s National HIV Program: Data From a Nationwide Laboratory Cohort. Clin Infect Dis. 2018;66(suppl_2):S111-S7. doi: 10.1093/cid/ciy045. PubMed PMID: 29514238; PMCID: PMC5850436.

Toribio M, Fitch KV, Sanchez L, Burdo TH, Williams KC, Sponseller CA, McCurdy Pate M, Aberg JA, Zanni MV, Grinspoon SK. Effects of pitavastatin and pravastatin on markers of immune activation and arterial inflammation in HIV. AIDS. 2017;31(6):797-806. doi: 10.1097/QAD.0000000000001427. PubMed PMID: 28252528; PMCID: PMC5382495.

Nixon DE, Bosch RJ, Chan ES, Funderburg NT, Hodder S, Lake JE, Lederman MM, Klingman KL, Aberg JA, Team ACTGSA. Effects of atorvastatin on biomarkers of immune activation, inflammation, and lipids in virologically suppressed, human immunodeficiency virus-1-infected individuals with low-density lipoprotein cholesterol <130 mg/dL (AIDS Clinical Trials Group Study A5275). J Clin Lipidol. 2017;11(1):61-9. doi: 10.1016/j.jacl.2016.09.017. PubMed PMID: 28391912; PMCID: PMC5407297.

Negredo E, Jimenez M, Puig J, Loste C, Perez-Alvarez N, Urrea V, Echeverria P, Bonjoch A, Clotet B, Blanco J. A randomized pilot trial to evaluate the benefit of the concomitant use of atorvastatin and Raltegravir on immunological markers in protease-inhibitor-treated subjects living with HIV. PLoS One. 2020;15(9):e0238575. doi: 10.1371/journal.pone.0238575. PubMed PMID: 32941476; PMCID: PMC7498036 =

Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4(12):977-87. doi: 10.1038/nrd1901. PubMed PMID: 16341063.

Bu DX, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol. 2011;22(3):165-70. doi: 10.1097/MOL.0b013e3283453e41. PubMed PMID: 21412153.

Hileman CO, Tangpricha V, Sattar A, McComsey GA. Baseline Vitamin D Deficiency Decreases the Effectiveness of Statins in HIV-Infected Adults on Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2017;74(5):539-47. doi: 10.1097/QAI.0000000000001281. PubMed PMID: 28045766; PMCID: PMC5340572.

Hileman CO, McComsey GA. Short Communication: The Effect of Rosuvastatin on Vascular Disease Differs by Smoking Status in Treated HIV Infection. AIDS Res Hum Retroviruses. 2018;34(3):282-5. doi: 10.1089/AID.2017.0164. PubMed PMID: 28974102; PMCID: PMC5863076.

Most read articles by the same author(s)