Résumés
Résumé
Les stratégies d’immunothérapie de l’infection par le VIH utilisant des cytokines ont pour objectifs d’interférer avec les mécanismes de dérégulation de l’homéostasie lymphocytaire T induits par le virus, de potentialiser les effets des antiviraux sur la restauration immunitaire et de mobiliser les réservoirs du virus. Les interleukines 2 et 7 (IL-2 et IL-7) sont les cytokines les plus prometteuses. Un bénéfice clinique potentiel de ces stratégies est l’arrêt des traitements antiviraux, dont la toxicité à long terme est une préoccupation majeure. Par ailleurs, les effets d’une telle immuno-intervention sur la régulation de l’homéostasie lymphocytaire T ou sur les fonctions immunologiques en présence du VIH nous renseignent également sur la physiopathologie de l’infection.
Summary
The theoretical objectives of cytokine therapies in HIV infection are to impact T cell homeostasis and/or to improve immune functions or the mobilization of the HIV reservoir. Among cytokines, IL-2 and IL-7 are promising agents under clinical evaluation. Intermittent administration of IL-2 is by far the furthest studied strategy in HIV infection. This cytokine increases CD4 T lymphocytes in HIV-infected individuals. Recent clinical data showed that this effect is sustained over years. IL-2 therapy induces a peripheral expansion of T cells as a consequence of prolonged survival of T cells and decreased immune activation. These effects suggest that a cytokine therapy may interfere with critical factors of HIV disease. Recent data provide arguments that IL-2 therapy improves immune functions in HIV-infected patients. Whether these effects may be translated into clinical benefits is under evaluation in ongoing phase III studies. The potential interest of IL-7 in the treatment of HIV-infection is based on its crucial role on T cell homeostasis both in thymic output and peripheral T proliferation and survival. Although no data in human are still available, recent studies provide arguments to assess this cytokine in HIV infection. Phase I studies are ongoing or planned.
Parties annexes
Références
- 1. Kovacs JA, Baseler M, Dewar RJ, et al. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection : a preliminary study. N Engl J Med 1995 ; 332 : 567-75.
- 2. Kovacs JA, Vogel S, Albert JM, et al. Sustained increases in CD4 counts with intermittent interleukin-2 therapy in HIV-infected patients with greater than 200 CD4 cells/mm3 : results of a randomized, controlled trial. N Engl J Med 1996 ; 335 : 1350-6.
- 3. Davey RT, Chaitt DG, Piscitelli SC, et al. Subcutaneous administration of interleukin-2 in HIV-1 infected persons. J Infect Dis 1997 ; 175 : 781-9.
- 4. Levy Y, Capitant C, Houhou S, et al. For the ANRS 048 study group. Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection : a randomised controlled trial. Lancet 1999 ; 353 : 1923-9.
- 5. Davey RT, Chaitt DJ, Albert JM, et al. A randomized trial of high- versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection. J Infect Dis 1999 ; 179 : 849-58.
- 6. Davey RT, Murphy RL, Graziano FM, et al. Immunologic and virologic effects of subcutaneous interleukin-2 in combination with antiretroviral therapy : a randomized controlled trial. JAMA 2000 ; 284 : 183-9.
- 7. Levy Y, Durier C, Krzysiek R, et al. Effects of interleukin-2 therapy combined with highly active antiretroviral treatment on immune restoration in HIV-1 infection : a randomized controlled trial. AIDS 2003 ; 17 : 343-51.
- 8. Arduino RC, Nannini EC, Rodriguez-Barradas M, et al. CD4 cell response to 3 doses of subcutaneous interleukin 2 : meta-analysis of 3 vanguard studies. Clin Infect Dis 2004 ; 39 : 115-22.
- 9. Gougeon ML, Rouzioux C, Liberman I, et al. Immunological and virological effects of long term IL-2 therapy in HIV-1-infected patient. AIDS 2001 ; 15 : 1729-31.
- 10. Farel CE, Chaitt DG, Hahn BK, et al. Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection. Blood 2004 ; 103 : 3282-6.
- 11. Sereti I, Martinez-Wilson H, Metcalf JA, et al. Long-term effect of intermittent interleukin-2 therapy in patients with HIV infection : characterization of a novel subset of CD4+/CD25+ T cells. Blood 2002 ; 100 : 2159-67.
- 12. Sereti I, Anthony KB, Martinez-Wilson H, et al. IL-2-induced CD4+ T cell expansion in HIV-infected patients is associated with long term decreases in T-cell proliferation. Blood 2004 ; 104 : 775-80.
- 13. Kovacs JA, Lempicki RA, Sidorov IA, et al. Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. J Clin Invest 2005 ; 115 : 2139-48.
- 14. Sereti I, Imamichi H, Natarajan V, et al. In vivo expansion of CD4+CD45RO-CD25+ T cells expressing foxP3 in IL-2 treated HIV-infected patients. J Clin Invest 2005 ; 115 : 1839-47.
- 15. Weiss L, Donkova-Petrini V, Aouba A, Levy Y. CD4+CD25+ regulatory T cells are detectable in peripheral blood of HIV-infected patients treated with IL-2. Rio de Janeiro : 3rd IAS Conference, 2005 : We.Pe.16.5.B06 (abstract).
- 16. Weiss, L, Donkova-Petrini, V, Caccavelli, L, et al. Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 2004 ; 101 : 3249-56.
- 17. Kinter A, Hennessey M, Bell A, et al. CD25+CD4+ regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4+ and CD8+ HIV-specific T cell immune responses in vitro and are associated with favourable clinical markers of disease status. J Exp Med 2004 ; 200 : 331-43.
- 18. Blattman JN, Grayson JM, Wherry EJ, et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat Med 2003 ; 9 : 540-7.
- 19. Valdez H, Mitsuyasu R, Landay A, et al. Interleukin-2 induces increases in CD4+ lymphocyte numbers but does not enhance responses to immunization : results of A5046s. J Infect Dis 2003 ; 187 : 320-5.
- 20. Levy Y, Gahery-Segard H, Durier C, et al. Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patient. AIDS 2005 ; 19 : 279-86.
- 21. Barouch DH, Santra S, Steenbeke TD, et al. Augmentation and suppression of immune responses to an HIV-1 DNA vaccine by plasmid cytokine/Ig administration. J Immunol 1998 ; 161 : 1875-82.
- 22. ESPRIT IL-2 trial (online) http://www.espritstudy.org.
- 23. SILCAAT study design (online) http://www.silcaatstudy.org.
- 24. Fry TJ, Mackall C. Interleukin-7 : from bench to clinic. Blood 2002 ; 99 : 3892-904.
- 25. Bolotin E, Annett G, Parkman R, Weinberg K. Serum levels of IL-7 in bone marrow transplant recipients : relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant 1999 ; 8 : 783-8.
- 26. Napolitano LA, Grant RM, Deeks SG, et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion. Implications for T cell homeostasis. Nat Med 2001 ; 7 : 73-9.
- 27. Smithgall MD, Wong JG, Critchett KE, Haffar OK. IL-7 up-regulates HIV-1 replication in naturally infected peripheral blood mononuclear cells. J Immunol 1996 ; 156 : 2324-30.
- 28. Steffens CM, Managlia EZ, Landay A, Al-Harthi L. Interleukin-7 treated naïve T cells can be productively infected by T-cell-adapted and primary isolates of human immunodeficiency virus 1. Blood 2002 ; 99 : 3310-8.
- 29. Fry TJ, Moniuszko M, Creekmore S, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 2003 ; 101 : 2294-9.
- 30. Nugeyre MT, Monceaux V, Beq S, et al. IL-7 stimulates T cell renewal without increasing viral replication in simian immunodeficiency virus-infected macaques. J Immunol 2003 ; 171 : 4447-53.
- 31. Wang FX, Xu Y, Sullivan J, et al. IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J Clin Invest 2005 ; 115 : 128-37.