Evidence for Persistent Monocyte and Immune Dysregulation After Prolonged Viral Suppression Despite Normalization of Monocyte Subsets, sCD14 and sCD163 in HIV-Infected Individuals
Article Sidebar
Main Article Content
Abstract
Background: People living with HIV on antiretroviral therapy (HIV/ART) experience excess non-AIDS comorbidities, and also remain at increased risk for certain infections and viral malignancies. Monocytes/macrophages are central to many of these comorbidities, and elevated plasma cytokines and immune activation during untreated infection are often incompletely reversed by ART and are also associated with comorbidities.
Methods: We investigated monocyte surface markers, gene expression, and plasma cytokines in 11 HIV-infected older individuals (median 53 years) who started therapy with low CD4 counts (median 129 cells/μl), with elevated hsCRP (≥ 2mg/L) despite long-term ART (median 7.4 years), along with matched controls.
Results: Frequency of monocyte subsets (based on CD14/CD16/CD163), were not different from controls, but surface expression of CD163 was increased (P = 0.021) while PD1 was decreased (P = 0.013) along with a trend for higher tissue factor (P = 0.096). As a group, HIV/ART participants had elevated plasma CCL2 (MCP-1; P = 0.0001), CXCL9 (MIG; P = 0.04), and sIL2R (P = 0.015), which were correlated, while sCD14 was not elevated. Principal component analysis of soluble markers revealed that 6/11 HIV/ART participants clustered with controls, while 5 formed a distinct group, driven by IL-10, CCL11, CXCL10, CCL2, CXCL9, and sIL2R. These individuals were significantly older than those clustering with controls. Transcriptomic analysis revealed multiple genes linked to immune functions including inflammation, immune cell development, and cell-cell signaling that were downregulated in HIV/ART monocytes and distinct from patterns in untreated subjects.
Conclusions: Long-term ART-treated individuals normalize monocyte subsets but exhibit immune dysregulation involving both aberrant inflammation and monocyte dysfunction, as well as inter-individual heterogeneity, suggesting complex mechanisms linking monocytes and HIV/ART comorbidities.
Downloads
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. Younas M, Psomas C, Reynes J, Corbeau P. Immune activation in the course of HIV-1 infection: Causes, phenotypes and persistence under therapy. HIV Med. 2016;17(2):89-105. PubMed PMID: 26452565. doi: 10.1111/hiv.12310
2. 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. Pubmed Central PMCID: 4126613. doi: 10.1016/B978-0-12-407707-2.00002-3
3. Hsu DC, Sereti I. Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection. Drugs. 2016;76(5):533-49. PubMed PMID: 26915027.
4. Kwan CK, Ernst JD. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev. 2011;24(2):351-76. PubMed PMID: 21482729. Pubmed Central PMCID: PMC3122491. doi: 10.1128/CMR.00042-10
5. Silverberg MJ, Lau B, Achenbach CJ, Jing YZ, Althoff KN, D'Souza G, Engels EA, Hessol NA, Brooks JT, Burchell AN, Gill MJ, Goedert JJ, Hogg R, Horberg MA, Kirk GD, Kitahata MM, Korthuis PT, Mathews WC, Mayor A, Modur SP, Napravnik S, Novak RM, Patel P, Rachlis AR, Sterling TR, Willig JH, Justice AC, Moore RD, Dubrow R, Databases IE. Cumulative Incidence of Cancer Among Persons With HIV in North America A Cohort Study. Ann Intern Med. 2015;163(7):507-+. PubMed PMID: WOS:000362496400004. doi: 10.7326/M14-2768
6. Shiels MS, Engels EA. Evolving epidemiology of HIV-associated malignancies. Curr Opin HIV AIDS. 2017;12(1):6-11. PubMed PMID: 27749369. Pubmed Central PMCID: PMC5240042. doi: 10.1097/COH.0000000000000327
7. McGuire JL, Gill AJ, Douglas SD, Kolson DL, group CHA-RTER, Grant I, Letendre SL, Ellis RJ, Marcotte TD, Franklin D, Jr., Ellis RJ, McCutchan JA, Alexander T, Letendre S, Capparelli E, Heaton RK, Atkinson JH, Woods SP, Dawson M, Smith DM, Wong JK, Fennema-Notestine C, Taylor MJ, Theilmann R, Gamst AC, Cushman C, Abramson I, Vaida F, Marcotte TD, von Jaeger R, McArthur J, Smith M, Morgello S, Simpson D, Mintz L, McCutchan JA, Toperoff W, Collier A, Marra C, Jones T, Gelman B, Head E, Clifford D, Al-Lozi M, Teshome M. Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neurovirol. 2015;21(4):439-48. PubMed PMID: 25776526.
8. Martin GE, Gouillou M, Hearps AC, Angelovich TA, Cheng AC, Lynch F, Cheng WJ, Paukovics G, Palmer CS, Novak RM, Jaworowski A, Landay AL, Crowe SM. Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women. PLoS One. 2013;8(1):e55279. PubMed PMID: 23365694. Pubmed Central PMCID: 3554695. doi: 10.1371/journal.pone.0055279
9. Zungsontiporn N, Tello RR, Zhang G, Mitchell BI, Budoff M, Kallianpur KJ, Nakamoto BK, Keating SM, Norris PJ, Ndhlovu LC, Souza SA, Shikuma CM, Chow DC. Non-Classical Monocytes and Monocyte Chemoattractant Protein-1 (MCP-1) Correlate with Coronary Artery Calcium Progression in Chronically HIV-1 Infected Adults on Stable Antiretroviral Therapy. PLoS One. 2016;11(2):e0149143. PubMed PMID: 26867220. Pubmed Central PMCID: PMC4750941. doi: 10.1371/journal.pone.0149143
10. 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, Group ISS. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011;203(6):780-90. PubMed PMID: 21252259.
11. Kusao I, Shiramizu B, Liang C-Y, Grove J, Agsalda M, Troelstrup D, Velasco V-N, Marshall A, Whitenack N, Shikuma C, Valcour V. Cognitive performance related to HIV-1-infected monocytes. J Neuropsychiatry Clin Neurosci. 2012;24(1):71-80. PubMed PMID: 22450616.
12. Kim W-K, Corey S, Alvarez X, Williams K. Monocyte/macrophage traffic in HIV and SIV encephalitis. J Leukoc Biol. 2003;74(5):650-6. PubMed PMID: 12960230.
13. Kamat A, Misra V, Cassol E, Ancuta P, Yan Z, Li C, Morgello S, Gabuzda D. A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy. PLoS One. 2012;7(2):e30881. PubMed PMID: 22363505.
14. Kaplan RC, Landay AL, Hodis HN, Gange SJ, Norris PJ, Young M, Anastos K, Tien PC, Xue X, Lazar J, Parrinello CM, Benning L, Tracy RP. Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment. J Acquir Immune Defic Syndr. 2012;60(4):359-68. PubMed PMID: 22592585.
15. 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.
16. Longenecker CT, Jiang Y, Orringer CE, Gilkeson RC, Debanne S, Funderburg NT, Lederman MM, Storer N, Labbato DE, McComsey GA. Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection. AIDS. 2014;28(7):969-77. PubMed PMID: 24691204.
17. Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, Letendre S, Rosenberg ES, Ellis RJ, Williams KC. Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J Infect Dis. 2011;204(1):154-63. PubMed PMID: 21628670.
18. Castley A, Berry C, French M, Fernandez S, Krueger R, Nolan D. Elevated plasma soluble CD14 and skewed CD16+ monocyte distribution persist despite normalisation of soluble CD163 and CXCL10 by effective HIV therapy: a changing paradigm for routine HIV laboratory monitoring? PLoS One. 2014;9(12):e115226. PubMed PMID: 25544986. Pubmed Central PMCID: PMC4278884. doi: 10.1371/journal.pone.0115226
19. Shikuma CM, Gangcuangco LMA, Killebrew DA, Libutti DE, Chow DC, Nakamoto BK, Liang CY, Milne CIP, Ndhlovu LC, Barbour JD, Shiramizu BT, Gerschenson M. The role of HIV and monocytes/macrophages in adipose tissue biology. J Acquir Immune Defic Syndr. 2014;65(2):151-9. PubMed PMID: 24091690.
20. 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.
21. Han J, Wang B, Han N, Zhao Y, Song C, Feng X, Mao Y, Zhang F, Zhao H, Zeng H. CD14(high)CD16(+) rather than CD14(low)CD16(+) monocytes correlate with disease progression in chronic HIV-infected patients. J Acquir Immune Defic Syndr. 2009;52(5):553-9. PubMed PMID: 19950429.
22. Kulkarni M, Bowman E, Gabriel J, Amburgy T, Mayne E, Zidar DA, Maierhofer C, Turner AN, Bazan JA, Koletar SL, Lederman MM, Sieg SF, Funderburg NT. Altered Monocyte and Endothelial Cell Adhesion Molecule Expression Is Linked to Vascular Inflammation in Human Immunodeficiency Virus Infection. Open Forum Infect Dis. 2016;3(4):ofw224. PubMed PMID: 28066794. Pubmed Central PMCID: PMC5198584. doi: 10.1093/ofid/ofw224
23. Gill AJ, Kolson DL. Chronic inflammation and the role for cofactors (hepatitis C, drug abuse, antiretroviral drug toxicity, aging) in HAND persistence. Curr HIV/AIDS Rep. 2014;11(3):325-35. PubMed PMID: 24929842. Pubmed Central PMCID: 4188391. doi: 10.1007/s11904-014-0210-3
24. Munoz-Moreno JA, Fumaz CR, Ferrer MJ, Prats A, Negredo E, Garolera M, Perez-Alvarez N, Molto J, Gomez G, Clotet B. Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients. AIDS Res Hum Retroviruses. 2008;24(10):1301-7. PubMed PMID: 18844464. doi: 10.1089/aid.2007.0310
25. Zhang S. A comprehensive evaluation of SAM, the SAM R-package and a simple modification to improve its performance. BMC bioinformatics. 2007;8:230. PubMed PMID: 17603887.
26. Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44-57. PubMed PMID: 19131956.
27. Mootha VK, Lindgren CM, Eriksson K-F, 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. PubMed PMID: 12808457.
28. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8. PubMed PMID: 18546601.
29. Almeida M, Cordero M, Almeida J, Orfao A. Persistent abnormalities in peripheral blood dendritic cells and monocytes from HIV-1-positive patients after 1 year of antiretroviral therapy. J Acquir Immune Defic Syndr. 2006;41(4):405-15. PubMed PMID: 16652047. doi: 10.1097/01.qai.0000209896.82255.d3
30. 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 syndrome. Blood. 2012;120(23):4599-608. PubMed PMID: 23065151. Pubmed Central PMCID: PMC3512236. doi: 10.1182/blood-2012-05-433946
31. Wong KL, Tai JJ, Wong WC, Han H, Sem X, Yeap WH, Kourilsky P, Wong SC. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood. 2011;118(5):e16-31. PubMed PMID: 21653326. doi: 10.1182/blood-2010-12-326355
32. Wong KL, Yeap WH, Tai JJ, Ong SM, Dang TM, Wong SC. The three human monocyte subsets: implications for health and disease. Immunol Res. 2012;53(1-3):41-57. PubMed PMID: 22430559. doi: 10.1007/s12026-012-8297-3
33. Hileman CO, Kinley B, Scharen-Guivel V, Melbourne K, Szwarcberg J, Robinson J, Lederman MM, McComsey GA. Differential Reduction in Monocyte Activation and Vascular Inflammation With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among HIV-Infected Individuals. J Infect Dis. 2015;212(3):345-54. PubMed PMID: 25583168.
34. Boasso A, Hardy AW, Landay AL, Martinson JL, Anderson SA, Dolan MJ, Clerici M, Shearer GM. PDL-1 upregulation on monocytes and T cells by HIV via type I interferon: restricted expression of type I interferon receptor by CCR5-expressing leukocytes. Clinical immunology (Orlando, Fla ). 2008;129(1):132-44. PubMed PMID: 18650129.
35. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy J-P, Douek DC, Haddad EK, Sekaly R-P. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16(4):452-9. PubMed PMID: 20208540.
36. Schechter ME, Andrade BB, He T, Richter GH, Tosh KW, Policicchio BB, Singh A, Raehtz KD, Sheikh V, Ma D, Brocca-Cofano E, Apetrei C, Tracy R, Ribeiro RM, Sher A, Francischetti IMB, Pandrea I, Sereti I. Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. Sci Transl Med. 2017;9(405). PubMed PMID: 28855397. Pubmed Central PMCID: PMC5755598. doi: 10.1126/scitranslmed.aam5441
37. 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. PubMed PMID: 22569268.
38. Knudsen TB, Ertner G, Petersen J, Moller HJ, Moestrup SK, Eugen-Olsen J, Kronborg G, Benfield T. Plasma Soluble CD163 Level Independently Predicts All-Cause Mortality in HIV-1-Infected Individuals. J Infect Dis. 2016. PubMed PMID: 27354366. doi: 10.1093/infdis/jiw263
39. Wilson EM, Singh A, Hullsiek KH, Gibson D, Henry WK, Lichtenstein K, Onen NF, Kojic E, Patel P, Brooks JT, Sereti I, Baker JV. Monocyte-activation phenotypes are associated with biomarkers of inflammation and coagulation in chronic HIV infection. J Infect Dis. 2014;210(9):1396-406. PubMed PMID: 24813472. Pubmed Central PMCID: 4207864. doi: 10.1093/infdis/jiu275
40. O'Halloran JA, Dunne E, Gurwith M, Lambert JS, Sheehan GJ, Feeney ER, Pozniak A, Reiss P, Kenny D, Mallon P. The effect of initiation of antiretroviral therapy on monocyte, endothelial and platelet function in HIV-1 infection. HIV Med. 2015;16(10):608-19. PubMed PMID: 26111187. doi: 10.1111/hiv.12270
41. Fu W, Sanders-Beer BE, Katz KS, Maglott DR, Pruitt KD, Ptak RG. Human immunodeficiency virus type 1, human protein interaction database at NCBI. Nucleic Acids Res. 2009;37(Database issue):D417-22. PubMed PMID: 18927109.
42. Ako-Adjei D, Fu W, Wallin C, Katz KS, Song G, Darji D, Brister JR, Ptak RG, Pruitt KD. HIV-1, human interaction database: current status and new features. Nucleic Acids Res. 2015;43(Database issue):D566-70. PubMed PMID: 25378338.
43. Sonza S, Mutimer HP, Oelrichs R, Jardine D, Harvey K, Dunne A, Purcell DF, Birch C, Crowe SM. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS. 2001;15(1):17-22. PubMed PMID: 11192864.
44. Wu JQ, Sasse TR, Saksena MM, Saksena NK. Transcriptome analysis of primary monocytes from HIV-positive patients with differential responses to antiretroviral therapy. Virol J. 2013;10:361. PubMed PMID: 24370116. Pubmed Central PMCID: 3877975. doi: 10.1186/1743-422X-10-361
45. Gekonge B, Giri MS, Kossenkov AV, Nebozyhn M, Yousef M, Mounzer K, Showe L, Montaner LJ. Constitutive gene expression in monocytes from chronic HIV-1 infection overlaps with acute Toll-like receptor induced monocyte activation profiles. PLoS One. 2012;7(7):e41153. PubMed PMID: 22815948. Pubmed Central PMCID: 3399809. doi: 10.1371/journal.pone.0041153
46. Giri MS, Nebozyhn M, Raymond A, Gekonge B, Hancock A, Creer S, Nicols C, Yousef M, Foulkes AS, Mounzer K, Shull J, Silvestri G, Kostman J, Collman RG, Showe L, Montaner LJ. Circulating monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance. J Immunol. 2009;182(7):4459-70. PubMed PMID: 19299747. Pubmed Central PMCID: 2776064. doi: 10.4049/jimmunol.0801450
47. Milush JM, Long BR, Snyder-Cappione JE, Cappione AJ, 3rd, York VA, Ndhlovu LC, Lanier LL, Michaelsson J, Nixon DF. Functionally distinct subsets of human NK cells and monocyte/DC-like cells identified by coexpression of CD56, CD7, and CD4. Blood. 2009;114(23):4823-31. PubMed PMID: 19805616. Pubmed Central PMCID: 2786291. doi: 10.1182/blood-2009-04-216374
48. Krasselt M, Baerwald C, Wagner U, Rossol M. CD56+ monocytes have a dysregulated cytokine response to lipopolysaccharide and accumulate in rheumatoid arthritis and immunosenescence. Arthritis Res Ther. 2013;15(5):R139. PubMed PMID: 24286519.
49. Barska K, Kwiatkowska W, Knysz B, Arczynska K, Karczewski M, Witkiewicz W. The role of the tissue factor and its inhibitor in the development of subclinical atherosclerosis in people living with HIV. PLoS One. 2017;12(7):e0181533. PubMed PMID: 28749986. Pubmed Central PMCID: PMC5531520. doi: 10.1371/journal.pone.0181533
50. Bianconi V, Sahebkar A, Atkin SL, Pirro M. The regulation and importance of monocyte chemoattractant protein-1. Curr Opin Hematol. 2018;25(1):44-51. PubMed PMID: 28914666. doi: 10.1097/MOH.0000000000000389
51. Bose S, Cho J. Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases. Arch Pharm Res. 2013;36(9):1039-50. PubMed PMID: 23771498. doi: 10.1007/s12272-013-0161-z
52. 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. PubMed PMID: 23922698. Pubmed Central PMCID: PMC3724935. doi: 10.1371/journal.pone.0069270
53. McKibben RA, Margolick JB, Grinspoon S, Li X, Palella FJ, Jr., Kingsley LA, Witt MD, George RT, Jacobson LP, Budoff M, Tracy RP, Brown TT, Post WS. Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection. J Infect Dis. 2015;211(8):1219-28. PubMed PMID: 25362192. Pubmed Central PMCID: PMC4402336. doi: 10.1093/infdis/jiu594
54. Dhillon NK, Williams R, Callen S, Zien C, Narayan O, Buch S. Roles of MCP-1 in development of HIV-dementia. Front Biosci. 2008;13:3913-8. PubMed PMID: 18508485. Pubmed Central PMCID: 2715276.
55. Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, Schifitto G, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Epstein LG, Marder K. Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology. 2004;63(11):2084-90. PubMed PMID: 15596754.
56. Floris-Moore M, Fayad ZA, Berman JW, Mani V, Schoenbaum EE, Klein RS, Weinshelbaum KB, Fuster V, Howard AA, Lo Y, Schecter AD. Association of HIV viral load with monocyte chemoattractant protein-1 and atherosclerosis burden measured by magnetic resonance imaging. AIDS. 2009;23(8):941-9. PubMed PMID: 19318907. Pubmed Central PMCID: 2786203. doi: 10.1097/QAD.0b013e328329c76b
57. Shikuma CM, Barbour JD, Ndhlovu LC, Keating SM, Norris PJ, Budoff M, Parikh N, Seto T, Gangcuangco LM, Ogata-Arakaki D, Chow D. Plasma monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels predict the presence of coronary artery calcium in HIV-infected individuals independent of traditional cardiovascular risk factors. AIDS Res Hum Retroviruses. 2014;30(2):142-6. PubMed PMID: 23984974. Pubmed Central PMCID: PMC3910454. doi: 10.1089/AID.2013.0183
58. Covino DA, Sabbatucci M, Fantuzzi L. The CCL2/CCR2 Axis in the Pathogenesis of HIV-1 Infection: A New Cellular Target for Therapy? Curr Drug Targets. 2016;17(1):76-110. PubMed PMID: 26687605. doi: 10.2174/138945011701151217110917
59. Di Prospero NA, Artis E, Andrade-Gordon P, Johnson DL, Vaccaro N, Xi L, Rothenberg P. CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Diabetes Obes Metab. 2014;16(11):1055-64. PubMed PMID: 24798870. doi: 10.1111/dom.12309
60. Kalliomaki J, Attal N, Jonzon B, Bach FW, Huizar K, Ratcliffe S, Eriksson B, Janecki M, Danilov A, Bouhassira D, Group APS. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain. 2013;154(5):761-7. PubMed PMID: 23523116. doi: 10.1016/j.pain.2013.02.003
61. Lalezari J, Gathe J, Brinson C, Thompson M, Cohen C, Dejesus E, Galindez J, Ernst JA, Martin DE, Palleja SM. Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in HIV-1-infected, treatment-experienced, CCR5 antagonist-naive subjects. J Acquir Immune Defic Syndr. 2011;57(2):118-25. PubMed PMID: 21317794. doi: 10.1097/QAI.0b013e318213c2c0
62. Sabbatucci M, Covino DA, Purificato C, Mallano A, Federico M, Lu J, Rinaldi AO, Pellegrini M, Bona R, Michelini Z, Cara A, Vella S, Gessani S, Andreotti M, Fantuzzi L. Endogenous CCL2 neutralization restricts HIV-1 replication in primary human macrophages by inhibiting viral DNA accumulation. Retrovirology. 2015;12:4. PubMed PMID: 25608886. Pubmed Central PMCID: PMC4314729. doi: 10.1186/s12977-014-0132-6
63. Oliver BG, Elliott JH, Price P, Phillips M, Cooper DA, French MA. Tuberculosis After Commencing Antiretroviral Therapy for HIV Infection Is Associated With Elevated CXCL9 and CXCL10 Responses to Mycobacterium tuberculosis Antigens. Jaids-Journal of Acquired Immune Deficiency Syndromes. 2012;61(3):287-92. PubMed PMID: WOS:000310519300009. doi: 10.1097/QAI.0b013e31826445ef
64. Chaturvedi S, Frame P, Newman SL. Macrophages from human immunodeficiency virus-positive persons are defective in host defense against Histoplasma capsulatum. J Infect Dis. 1995;171(2):320-7. PubMed PMID: 7844367. doi: 10.1093/infdis/171.2.320
65. Eales LJ, Moshtael O, Pinching AJ. Microbicidal activity of monocyte derived macrophages in AIDS and related disorders. Clin Exp Immunol. 1987;67(2):227-35. PubMed PMID: 3111759. Pubmed Central PMCID: PMC1542592.
66. Kanterman J, Sade-Feldman M, Baniyash M. New insights into chronic inflammation-induced immunosuppression. Semin Cancer Biol. 2012;22(4):307-18. PubMed PMID: 22387003. doi: 10.1016/j.semcancer.2012.02.008
67. Baniyash M, Sade-Feldman M, Kanterman J. Chronic inflammation and cancer: suppressing the suppressors. Cancer Immunol Immunother. 2014;63(1):11-20. PubMed PMID: 23990173. doi: 10.1007/s00262-013-1468-9
68. Wu JQ, Sasse TR, Wolkenstein G, Conceicao V, Saksena MM, Soedjono M, Perera SS, Wang B, Dwyer DE, Saksena NK. Transcriptome analysis of primary monocytes shows global down-regulation of genetic networks in HIV viremic patients versus long-term non-progressors. Virology. 2013;435(2):308-19. PubMed PMID: WOS:000313459200013. doi: 10.1016/j.virol.2012.10.026
69. Pulliam L, Sun B, Rempel H. Invasive chronic inflammatory monocyte phenotype in subjects with high HIV-1 viral load. J Neuroimmunol. 2004;157(1-2):93-8. PubMed PMID: WOS:000225869400013. doi: 10.1016/j.jneuroim.2004.08.039
70. Van den Bergh R, Florence E, Vlieghe E, Boonefaes T, Grooten J, Houthuys E, Tran HTT, Gali Y, De Baetselier P, Vanham G, Raes G. Transcriptome analysis of monocyte-HIV interactions. Retrovirology. 2010;7. PubMed PMID: WOS:000280297100001. Artn 53. doi: 10.1186/1742-4690-7-53
71. Wu JQ, Sasse TR, Saksena MM, Saksena NK. Transcriptome analysis of primary monocytes from HIV-positive patients with differential responses to antiretroviral therapy. Virol J. 2013;10. PubMed PMID: WOS:000330052200001. Artn 361. doi: 10.1186/1743-422x-10-361
72. Van den Bergh R, Florence E, Vlieghe E, Boonefaes T, Grooten J, Houthuys E, Tran HT, Gali Y, De Baetselier P, Vanham G, Raes G. Transcriptome analysis of monocyte-HIV interactions. Retrovirology. 2010;7:53. PubMed PMID: 20546557. Pubmed Central PMCID: PMC2900222. doi: 10.1186/1742-4690-7-53
FootnotesSubmitted September 23, 2019 | Accepted November 21, 2019 | Published December 17, 2019Supplementary Materials
Supplementary Figure 1. Gating of monocyte subsets. Freshly isolated PBMCs from HIV+ and HIV- individuals were stained for monocyte surface markers and analyzed by flow cytometry. Representative dot plot showing monocyte subsets based on CD16 expression after gating on total CD14+ monocytes.
Supplementary Figure 2. Correlation analysis between soluble markers combining HIV/ART and HIV-negative participants. A Spearman correlation test was used to assess the significance of correlations between the measured parameters combining HIV/ART and HIV-negative participants. (A) Correlations between CXCL9, CCL2, CCL11, and IL-2R (sIL-2R). (B) Correlations between sCD14, CCL2, sCD163, and hsCRP. The correlation coefficient and significance values for each comparison are shown over each graph.
Supplementary Figure 3. Proportion of monocyte subsets expressing surface markers. (A) Percentage of classical (CD14++CD16-), (B) intermediate (CD14++CD16+), and (C) non-classical (CD14+CD16++) monocyte subsets from virally suppressed HIV/ART participants and matched HIV-negative controls expressing the indicated markers. Results are expressed as mean ± SE. P value is calculated using unpaired Mann Whitney U-test.
Supplementary Figure 4. Mean fluorescence intensity of surface markers on monocyte subsets. MFI of indicated markers on (A) classical (CD14++CD16-), (B) intermediate (CD14++CD16+), and (C) non-classical (CD14+CD16++) monocyte subsets from virally suppressed HIV/ART participants and matched HIV-negative controls. Results are expressed as mean ± SE. P value is calculated using unpaired Mann Whitney U-test.