Immunologic Effects of Maraviroc in HIV-Infected Patients with Severe CD4 Lymphopenia Starting Antiretroviral Therapy: A Sub-Study of the CADIRIS Trial

Main Article Content

Pablo Francisco Belaunzarán-Zamudio
Livio Azzoni
David H. Canaday
Yanink N. Caro-Vega
Brian Clagett
Mohammed S Rassool
Benigno Rodriguez
Ian Sanne
Irini Sereti
Juan G. Sierra-Madero
Michael M. Lederman


Background:  We aimed to describe the mechanisms of immunological recovery and the effects of blocking CCR5 in patients starting ART with advanced HIV-infection. Methods: Sub-study of a randomized, double-blind, clinical trial where patients starting ART with CD4 counts <100cells/uL received maraviroc or placebo. CD4 and CD8 maturation phenotypes, PD-1 and CCR5 expression, and activation indices were characterized at weeks 0, 4, 12, 24 and 48. CD4 and CD8 reactivity with peptides of CMV, MTb and with Staphylococcal enterotoxin B (SEB) was assessed by intracellular expression of IFNγ, TNFα and CD40 ligand at weeks 0, 4 and 12 of ART. Results: Forty patients were studied (Maraviroc=22; placebo=18). Sustained increases in CD8 were observed in the maraviroc arm. Significant, increases in the proportions of circulating CCR5+ CD4 and CD8; in central memory and effector memory CD8; and in the proportion of activated CD4 and CD8 were observed at week 4 in the maraviroc arm. T cell responses to CMV, MTb and SEB did not differ by treatment arms.  Conclusions: The higher increases of CCR5+ and activated CD4 and CD8 in circulation without affecting CD4 recovery or antigen-specific T-cell responses strongly suggests an increased retention in circulation of CCR5+ cells due to maraviroc. 


Download data is not yet available.

Article Details

Author Biography

Pablo Francisco Belaunzarán-Zamudio, Universidad Nacional Autónoma de México Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

Head of HIV Clinic

Departamento de Infectología


1. When To Start Consortium, Sterne JA, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, Funk MJ, Geskus RB, Gill J, Dabis F, Miro JM, Justice AC, Ledergerber B, Fatkenheuer G, Hogg RS, Monforte AD, Saag M, Smith C, Staszewski S, Egger M, Cole SR. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373(9672):1352-63. PubMed PMID: 19361855. Pubmed Central PMCID: 2670965. doi: 10.1016/S0140-6736(09)60612-7

2. Sterling TR, Lau B, Zhang J, Freeman A, Bosch RJ, Brooks JT, Deeks SG, French A, Gange S, Gebo KA, John Gill M, Horberg MA, Jacobson LP, Kirk GD, Kitahata MM, Klein MB, Martin JN, Rodriguez B, Silverberg MJ, Willig JH, Eron JJ, Goedert JJ, Hogg RS, Justice AC, McKaig RG, Napravnik S, Thorne J, Moore RD, North American ACCoR, Design of the International Epidemiologic Databases to Evaluate AIDS (IeDEA). Risk factors for tuberculosis after highly active antiretroviral therapy initiation in the United States and Canada: implications for tuberculosis screening. J Infect Dis. 2011;204(6):893-901. PubMed PMID: 21849286. Pubmed Central PMCID: 3156918. doi: 10.1093/infdis/jir421

3. Sanne IM, Westreich D, Macphail AP, Rubel D, Majuba P, Van Rie A. Long term outcomes of antiretroviral therapy in a large HIV/AIDS care clinic in urban South Africa: a prospective cohort study. J Int AIDS Soc. 2009;12:38. PubMed PMID: 20017918. Pubmed Central PMCID: 2811100. doi: 10.1186/1758-2652-12-38

4. Sabin CA, Smith CJ, Gumley H, Murphy G, Lampe FC, Phillips AN, Prinz B, Youle M, Johnson MA. Late presenters in the era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy. AIDS. 2004;18(16):2145-51. PubMed PMID: 15577647.

5. Tuboi SH, Pacheco AG, Harrison LH, Stone RA, May M, Brinkhof MW, Dabis F, Egger M, Nash D, Bangsberg D, Braitstein P, Yiannoutsos CT, Wood R, Sprinz E, Schechter M, IeDEA Ao. Mortality associated with discordant responses to antiretroviral therapy in resource-constrained settings. J Acquir Immune Defic Syndr. 2010;53(1):70-7. PubMed PMID: 20035163. Pubmed Central PMCID: 2802453. doi: 10.1097/QAI.0b013e3181c22d19

6. Carriquiry G, Fink V, Koethe JR, Giganti MJ, Jayathilake K, Blevins M, Cahn P, Grinsztejn B, Wolff M, Pape JW, Padgett D, Madero JS, Gotuzzo E, McGowan CC, Shepherd BE. Mortality and loss to follow-up among HIV-infected persons on long-term antiretroviral therapy in Latin America and the Caribbean. J Int AIDS Soc. 2015;18:20016. PubMed PMID: 26165322. Pubmed Central PMCID: 4499577. doi: 10.7448/IAS.18.1.20016

7. Lichtenstein KA, Armon C, Buchacz K, Chmiel JS, Buckner K, Tedaldi EM, Wood K, Holmberg SD, Brooks JT, Investigators HIVOS. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. Clin Infect Dis. 2010;51(4):435-47. PubMed PMID: 20597691. doi: 10.1086/655144

8. Hessol NA, Martinez-Maza O, Levine AM, Morris A, Margolick JB, Cohen MH, Jacobson LP, Seaberg EC. Lung cancer incidence and survival among HIV-infected and uninfected women and men. AIDS. 2015;29(10):1183-93. PubMed PMID: 25888645. Pubmed Central PMCID: 4457511. doi: 10.1097/QAD.0000000000000690

9. Abraham AG, Li X, Jacobson LP, Estrella MM, Evans RW, Witt MD, Phair J. Antiretroviral therapy-induced changes in plasma lipids and the risk of kidney dysfunction in HIV-infected men. AIDS Res Hum Retroviruses. 2013;29(10):1346-52. PubMed PMID: 23758574. Pubmed Central PMCID: 3785801. doi: 10.1089/AID.2012.025310.1089/AID.2012.0253

10. Grant PM, Kitch D, McComsey GA, Dube MP, Haubrich R, Huang J, Riddler S, Tebas P, Zolopa AR, Collier AC, Brown TT. Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation. Clin Infect Dis. 2013;57(10):1483-8. PubMed PMID: 23943825. Pubmed Central PMCID: 3805172. doi: 10.1093/cid/cit538

11. O'Connor JL, Smith CJ, Lampe FC, Hill T, Gompels M, Hay P, Chadwick D, Fisher M, Ainsworth J, Gilson R, Mackie N, Anderson J, Orkin C, Nelson M, Kegg S, Leen C, Palfreeman A, Post F, Johnson M, Sabin CA, Phillips AN, Committee UKCHCSS. Failure to achieve a CD4+ cell count response on combination antiretroviral therapy despite consistent viral load suppression. AIDS. 2014;28(6):919-24. PubMed PMID: 24335482. doi: 10.1097/QAD.0000000000000165

12. Li X, Margolick JB, Jamieson BD, Rinaldo CR, Phair JP, Jacobson LP. CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2011;57(5):421-8. PubMed PMID: 21602699. Pubmed Central PMCID: 3293185. doi: 10.1097/QAI.0b013e31821e9f21

13. Engsig FN, Gerstoft J, Kronborg G, Larsen CS, Pedersen G, Roge B, Jensen J, Nielsen LN, Obel N. Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: a cohort study. BMC Infect Dis. 2010;10:318. PubMed PMID: 21044307. Pubmed Central PMCID: 2988053. doi: 10.1186/1471-2334-10-318

14. van Griensven J, Thai S. Predictors of immune recovery and the association with late mortality while on antiretroviral treatment in Cambodia. Trans R Soc Trop Med Hyg. 2011;105(12):694-703. PubMed PMID: 21962614. doi: 10.1016/j.trstmh.2011.08.007

15. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997;277(5322):112-6. PubMed PMID: 9204894.

16. Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, Leonard JM, Danner SA, Miedema F, Schellekens PT. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med. 1998;4(2):208-14. PubMed PMID: 9461195.

17. Al-Harthi L, Voris J, Patterson BK, Becker S, Eron J, Smith KY, D'Amico R, Mildvan D, Snidow J, Pobiner B, Yau L, Landay A. Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients. HIV Med. 2004;5(1):55-65. PubMed PMID: 14731171.

18. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, Ferre AL, Hayes TL, Somsouk M, Hsue PY, Van Natta ML, Meinert CL, Lederman MM, Hatano H, Jain V, Huang Y, Hecht FM, Martin JN, McCune JM, Moreno S, Deeks SG. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014;10(5):e1004078. PubMed PMID: 24831517. Pubmed Central PMCID: 4022662. doi: 10.1371/journal.ppat.1004078

19. Serrano-Villar S, Moreno S, Fuentes-Ferrer M, Sanchez-Marcos C, Avila M, Sainz T, de Villar NG, Fernandez-Cruz A, Estrada V. The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery. HIV Med. 2014;15(1):40-9. PubMed PMID: 24007533. doi: 10.1111/hiv.12081

20. Benito JM, Lopez M, Lozano S, Ballesteros C, Martinez P, Gonzalez-Lahoz J, Soriano V. Differential upregulation of CD38 on different T-cell subsets may influence the ability to reconstitute CD4+ T cells under successful highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2005;38(4):373-81. PubMed PMID: 15764953.

21. Sierra-Madero JG, Ellenberg SS, Rassool MS, Tierney A, Belaunzaran-Zamudio PF, Lopez-Martinez A, Pineirua-Menendez A, Montaner LJ, Azzoni L, Benitez CR, Sereti I, Andrade-Villanueva J, Mosqueda-Gomez JL, Rodriguez B, Sanne I, Lederman MM, team Cs. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. Lancet HIV. 2014;1(2):e60-7. PubMed PMID: 26423989. doi: 10.1016/S2352-3018(14)70027-X

22. HIV/AIDS Network Coordination. ACTG/IMPAACT Laboratory Manual. Available at:

23. NIH AIDS Reagent Program [internet]. Bethesda: Pathogenesis and Basic Research Branch, Division of AIDS NIAID. [updated 2014 Dec 9; cited 2016 Oct 31]. Available from:

24. NIH AIDS Reagent Program [internet]. Bethesda: Pathogenesis and Basic Research Branch, Division of AIDS NIAID. [updated 2014 Dec 9; cited 2016 Oct 31]. Available from:

25. NIH AIDS Reagent Program [internet]. Bethesda: Pathogenesis and Basic Research Branch, Division of AIDS NIAID. [updated 2014 Dec 9; cited 2016 Oct 31]. Available from:

26. NIH AIDS Reagent Program [internet]. Bethesda: Pathogenesis and Basic Research Branch, Division of AIDS NIAID. [updated 2014 Dec 9; cited 2016 Oct 31]. Available from:

27. NIH AIDS Reagent Program [internet]. Bethesda: Pathogenesis and Basic Research Branch, Division of AIDS NIAID. [updated 2014 Dec 9; cited 2016 Oct 31]. Available from:

28. Chattopadhyay PK, Yu J, Roederer M. A live-cell assay to detect antigen-specific CD4+ T cells with diverse cytokine profiles. Nat Med. 2005;11(10):1113-7. PubMed PMID: 16186817. doi: 10.1038/nm1293

29. Frentsch M, Arbach O, Kirchhoff D, Moewes B, Worm M, Rothe M, Scheffold A, Thiel A. Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat Med. 2005;11(10):1118-24. PubMed PMID: 16186818. doi: 10.1038/nm1292

30. World Medical Association. Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013.

31. Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV, Nasta SD, Goldstein SC, Stadtmauer EA, Smith J, Bailey S, Mick R, Heitjan DF, Emerson SG, Hoxie JA, Vonderheide RH, Porter DL. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med. 2012;367(2):135-45. PubMed PMID: 22784116. Pubmed Central PMCID: 3568501. doi: 10.1056/NEJMoa1201248

32. van Lelyveld SF, Drylewicz J, Krikke M, Veel EM, Otto SA, Richter C, Soetekouw R, Prins JM, Brinkman K, Mulder JW, Kroon F, Middel A, Symons J, Wensing AM, Nijhuis M, Borghans JA, Tesselaar K, Hoepelman AI, group Ms. Maraviroc Intensification of cART in Patients with Suboptimal Immunological Recovery: A 48-Week, Placebo-Controlled Randomized Trial. PLoS One. 2015;10(7):e0132430. PubMed PMID: 26208341. Pubmed Central PMCID: 4514679. doi: 10.1371/journal.pone.0132430

33. 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. Pubmed Central PMCID: 3685899. doi: 10.1182/blood-2012-06-436345

34. Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, Huerre M, Dromer F, Dupont B, Lortholary O. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS. 2006;20(1):119-21. PubMed PMID: 16327328.

35. Meditz AL, Haas MK, Folkvord JM, Melander K, Young R, McCarter M, Mawhinney S, Campbell TB, Lie Y, Coakley E, Levy DN, Connick E. HLA-DR+ CD38+ CD4+ T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo. J Virol. 2011;85(19):10189-200. PubMed PMID: 21813616. Pubmed Central PMCID: 3196402. doi: 10.1128/JVI.02529-10

36. Patro SC, Azzoni L, Joseph J, Fair MG, Sierra-Madero JG, Rassool MS, Sanne I, Montaner LJ. Antiretroviral therapy in HIV-1-infected individuals with CD4 count below 100 cells/mm3 results in differential recovery of monocyte activation. J Leukoc Biol. 2016;100(1):223-31. PubMed PMID: 26609048. Pubmed Central PMCID: 4946615. doi: 10.1189/jlb.5AB0915-406R

Most read articles by the same author(s)

<< < 1 2