CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV-positive patients

Journal of the International AIDS Society

Volumn 18, Issue 1, 2015, Pages

  Lu, Wei ^a,b,c   Mehraj, Vikram ^a,b   Vyboh, Kishanda ^a,b   Cao, Wei ^a,b,c   Li, Taisheng ^c   Routy, Jean Pierre ^a,b  

^a MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

^b RESEARCH INSTITUTE OF THE MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

^c PEKING UNION MEDICAL COLLEGE HOSPITAL   (China)

Author keywords

CD4:CD8 ratio; HIV infection; Immune dysfunction; Inflammation; Viral reservoir

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; BETA 2 MICROGLOBULIN; IMMUNOGLOBULIN A; SOLUBLE INTERLEUKIN 2 RECEPTOR; BIOLOGICAL MARKER;

AGING; ANTIVIRAL THERAPY; CD4 CD8 RATIO; CD4 LYMPHOCYTE COUNT; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; DISEASE COURSE; EFFECTOR CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOPATHOLOGY; INFLAMMATION; LYMPHOCYTE DIFFERENTIATION; MEMORY T LYMPHOCYTE; NONHUMAN; OUTCOME ASSESSMENT; PRIORITY JOURNAL; PROGNOSIS; REVIEW; T LYMPHOCYTE SUBPOPULATION; TREATMENT RESPONSE; VIRUS CARRIER; VIRUS LOAD; VIRUS REPLICATION; ADULT; HIV INFECTIONS; IMMUNOLOGY; VIROLOGY;

ADULT; BIOMARKERS; CD4-CD8 RATIO; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; DISEASE PROGRESSION; HIV INFECTIONS; HUMANS; VIRAL LOAD;

EID: 84936797601     PISSN: None     EISSN: 17582652     Source Type: Journal    
DOI: 10.7448/IAS.18.1.20052     Document Type: Review

References (67)

1. Frazer IH, Mackay IR, Crapper RM, Jones B, Gust ID, Sarngadharan MG, et al. Immunological abnormalities in asymptomatic homosexual men: correlation with antibody to HTLV-III and sequential changes over two years. Q J Med. 1986;61(234):921-33.
2. Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet. 2013;382(9903):1525-33.
3. Vyboh K, Jenabian M-A, Mehraj V, Routy J-P. HIV and the gut microbiota, partners in crime: breaking the vicious cycle to unearth new therapeutic targets. J Immunol Res. 2015;2015:314127.
4. Serrano-Villar S, Perez-Elias MJ, Dronda F, Casado JL, Moreno A, Royuela A, et al. Increased risk of serious non-AIDS-related events in HIV-infected subjects on antiretroviral therapy associated with a low CD4/CD8 ratio. PLoS One. 2014;9(1):85798.
5. Mudd JC, Lederman MM. CD8 T cell persistence in treated HIV infection. Curr Opin HIV AIDS. 2014;9(5):500-5.
6. Taylor JM, Fahey JL, Detels R, Giorgi JV. CD4 percentage, CD4 number, and CD4:CD8 ratio in HIV infection: which to choose and how to use. J Acquir Immune Defic Syndr. 1989;2(2):114-24.
7. Fahey JL, Taylor JM, Detels R, Hofmann B, Melmed R, Nishanian P, et al. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med. 1990;322(3):166-72.
8. Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16(2):83-92.
9. Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179(4):859-70.
10. Clifford GM, Rickenbach M, Lise M, Dal Maso L, Battegay M, Bohlius J, et al. Hodgkin lymphoma in the Swiss HIV Cohort Study. Blood. 2009; 113(23):5737-42.
11. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4. Arch Intern Med. 2010;170(14):1228-38.
12. Syrjala H, Surcel HM, Ilonen J. Low CD4/CD8 T lymphocyte ratio in acute myocardial infarction. Clin Exp Immunol. 1991;83(2):326-8.
13. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, et al. 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.
14. Kaufmann GR, Perrin L, Pantaleo G, Opravil M, Furrer H, Telenti A, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. Arch Intern Med. 2003;163(18):2187-95.
15. 3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46(1):72-7.
16. Gaardbo JC, Hartling HJ, Gerstoft J, Nielsen SD. Incomplete immune recovery in HIV infection: mechanisms, relevance for clinical care, and possible solutions. Clin Dev Immunol. 2012;2012:670957.
17. Jimenez E, Vicente A, Sacedon R, Munoz JJ, Weinmaster G, Zapata AG, et al. Distinct mechanisms contribute to generate and change the CD4:CD8 cell ratio during thymus development: a role for the Notch ligand, Jagged1. J Immunol. 2001;166(10):5898-908.
18. Kosmrlj A, Read EL, Qi Y, Allen TM, Altfeld M, Deeks SG, et al. Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature. 2010;465(7296):350-4.
19. Routy JP, Angel J, Patel M, Kanagaratham C, Radzioch D, Kema I, et al. Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV-infected patients receiving antiretroviral therapy. HIV Med. 2015;16(1):48-56.
20. Tinago W, Coghlan E, Macken A, McAndrews J, Doak B, Prior-Fuller C, et al. Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naive and memory T-cell subsets. PLoS One. 2014;9(5):97011.
21. Torti C, Prosperi M, Motta D, Digiambenedetto S, Maggiolo F, Paraninfo G, et al. Factors influencing the normalization of CD4 T-cell count, percentage and CD4 + /CD8+ T-cell ratio in HIV-infected patients on long-term suppressive antiretroviral therapy. Clin Microbiol Infect. 2012;18(5):449-58.
22. Buggert M, Frederiksen J, Noyan K, Svard J, Barqasho B, Sonnerborg A, et al. Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection. J Immunol. 2014;192(5):2099-108.
23. Ndumbi P, Falutz J, Pant Pai N, Tsoukas CM. Delay in cART initiation results in persistent immune dysregulation and poor recovery of T-cell phenotype despite a decade of successful HIV suppression. PLoS One. 2014;9(4):e94018.
24. Helleberg M, Kronborg G, Ullum H, Ryder LP, Obel N, Gerstoft J. Course and clinical significance of CD8+ T-cell counts in a large cohort of HIV-infected individuals. 2015;211(11):1726-34.
25. Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection. Blood. 2011;117(21):5582-90.
26. Mussini C, Lorenzini P, Cozzi-Lepri A, Lapadula G, Marchetti G, Nicastri E, et al. CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study. Lancet HIV. 2015;2(3):e98-e106.
27. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815-26.
28. Emu B, Moretto WJ, Hoh R, Krone M, Martin JN, Nixon DF, et al. Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease. PLoS One. 2014;9(1):e85613.
29. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217-26.
30. Saracino A, Bruno G, Scudeller L, Volpe A, Caricato P, Ladisa N, et al. Chronic inflammation in a long-term cohort of HIV-infected patients according to the normalization of the CD4:CD8 ratio. AIDS Res Hum Retroviruses. 2014;30(12):1178-84.
31. Serrano-Villar S, Gutierrez C, Vallejo A, Hernandez-Novoa B, Diaz L, Abad Fernandez M, et al. The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression. J Infect. 2013;66(1):57-66.
32. Wallach D, Kang TB, Kovalenko A. Concepts of tissue injury and cell death in inflammation: a historical perspective. Nat Rev Immunol. 2014;14(1):51-9.
33. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol. 2008;214(2):231-41.
34. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011;62:141-55.
35. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350-4.
36. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16(4):452-9.
37. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12(10):1198-202.
38. Sereti I, Estes JD, Thompson WL, Morcock DR, Fischl MA, Croughs T, et al. Decreases in colonic and systemic inflammation in chronic HIV infection after IL-7 administration. PLoS Pathog. 2014;10(1):e1003890.
39. Sainz T, Serrano-Villar S, Diaz L, Gonzalez Tome MI, Gurbindo MD, de Jose MI, et al. The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults. AIDS. 2013;27(9):1513-6.
40. Favre D, Mold J, Hunt PW, Kanwar B, Loke P, Seu L, et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med. 2010;2(32):32ra6.
41. Jenabian MA, Patel M, Kema I, Kanagaratham C, Radzioch D, Thebault P, et al. Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers. PLoS One. 2013;8(10):78146.
42. Jenabian MA, El-Far M, Vyboh K, Kema I, Costiniuk CT, Thomas R, et al. Immunosuppressive tryptophan catabolism and gut mucosal dysfunction following early HIV infection. J Infect Dis. 2015.
43. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, et al. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014;210(8):1248-59.
44. Hileman CO, Kinley B, Scharen-Guivel V, Melbourne K, Szwarcberg J, Robinson J, et al. Differential reduction in monocyte activation and vascular inflammation with integrase inhibitor-based initial antiretroviral therapy. J Infect Dis. 2015.
45. Mehraj V, Jenabian MA, Vyboh K, Routy JP. Immune suppression by myeloid cells in HIV infection: new targets for immunotherapy. Open AIDS J. 2014;8:66-78.
46. Leung V, Gillis J, Raboud J, Cooper C, Hogg RS, Loutfy MR, et al. Predictors of CD4:CD8 ratio normalization and its effect on health outcomes in the era of combination antiretroviral therapy. PLoS One. 2013;8(10):77665.
47. Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G, et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol. 2006;176(4):2645-53.
48. Strindhall J, Nilsson BO, Lofgren S, Ernerudh J, Pawelec G, Johansson B, et al. No Immune risk profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol. 2007;42(8):753-61.
49. Wikby A, Maxson P, Olsson J, Johansson B, Ferguson FG. Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev. 1998;102(2-3):187-98.
50. Kroger L, Vahasalo P, Tynjala P, Aalto K, Saila H, Malin M, et al. [Medical treatment of juvenile idiopathic arthritis]. Duodecim. 2012;128(5):477-86.
51. Smith GH, Boulassel MR, Klien M, Gilmore N, MacLeod J, LeBlanc R, et al. Virologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients. HIV Clin Trials. 2005;6(2):63-72.
52. Rickabaugh TM, Jamieson BD. A challenge for the future: aging and HIV infection. Immunol Res. 2010;48(1-3):59-71.
53. Zapata HJ, Shaw AC. Aging of the human innate immune system in HIV infection. Curr Opin Immunol. 2014;29:127-36.
54. Menozzi M, Zona S, Santoro A, Carli F, Stentarelli C, Mussini C, et al. CD4/CD8 ratio is not predictive of multi-morbidity prevalence in HIV-infected patients but identify patients with higher CVD risk. J Int AIDS Soc. 2014;17(4 Suppl 3): 19709.
55. Bernal E, Serrano J, Perez A, Valero S, Garcia E, Marin I, et al. The CD4:CD8 ratio is associated with IMT progression in HIV-infected patients on antiretroviral treatment. J Int AIDS Soc. 2014;17(4 Suppl 3):19723.
56. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA. 1997;94(24):13193-7.
57. Davey RT, Jr., Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA. 1999;96(26):15109-14.
58. Autran B, Descours B, Bacchus C. Immune control of HIV-1 reservoirs. Curr Opin HIV AIDS. 2013;8(3):204-10.
59. International ASSWGoHIVC, Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, et al. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol. 2012;12(8):607-14.
60. Chun TW, Justement JS, Pandya P, Hallahan CW, McLaughlin M, Liu S, et al. Relationship between the size of the human immunodeficiency virus type 1 (HIV-1) reservoir in peripheral blood CD4+ T cells and CD4+ :CD8+ T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy. J Infect Dis. 2002;185(11):1672-6.
61. Boulassel MR, Chomont N, Pai NP, Gilmore N, Sekaly RP, Routy JP. CD4 T cell nadir independently predicts the magnitude of the HIV reservoir after prolonged suppressive antiretroviral therapy. J Clin Virol. 2012;53(1):29-32.
62. Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z, et al. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med. 2014;20(2):139-42.
63. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15(8):893-900.
64. Cockerham LR, Siliciano JD, Sinclair E, O'Doherty U, Palmer S, Yukl SA, et al. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells. PLoS One. 2014;9(10):e110731.
65. Barouch DH, Deeks SG. Immunologic strategies for HIV-1 remission and eradication. Science. 2014;345(6193):169-74.
66. Hocqueloux L, Avettand-Fenoel V, Jacquot S, Prazuck T, Legac E, Melard A, et al. Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts. J Antimicrob Chemother. 2013;68(5):1169-78.
67. Thornhill J, Inshaw J, Oomeer S, Kaleebu P, Cooper D, Ramjee G, et al. Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection. J Int AIDS Soc. 2014;17(4 Suppl 3):19480.