IL-2 immunotherapy in chronically SIV-infected Rhesus Macaques

Garibal Julie, Laforge Mireille, Silvestre Ricardo, Mouhamad Shahul, Campillo-Gimenez Laure, Lévy Yves, Estaquier, Estaquier Jérôme

Description

Despite inducing a sustained increase in CD4+ T cell counts, intermittent recombinant IL-2 (rIL-2) therapy did not confer a better clinical outcome in HIV-infected patients enrolled in large phase III clinical trials ESPRIT and SILCAAT. Several hypotheses were evoked to explain these discrepancies. Here, we investigated the impact of low and high doses of IL-2 in Rhesus macaques of Chinese origin infected with SIVmac251 in the absence of antiretroviral therapy (ART). Results We demonstrated that rIL-2 induced a dose dependent expansion of CD4+ and CD8+ T cells without affecting viral load. rIL-2 increased CD4 and CD8 Treg cells as defined by the expression of CD25 high FoxP3 + CD127 low . We also showed that rIL-2 modulated spontaneous and Fas-mediated CD4 + and CD8 + T cell apoptosis. The higher dose exhibited a dramatic pro-apoptotic effect on both CD4 + and CD8 + T cell populations. Finally, all the animals treated with rIL-2 developed a wasting syndrome in the month following treatment simultaneously to a dramatic decrease of circulating effector T cells. Conclusion These data contribute to the understanding of the homeostatic and dosage effects of IL-2 in the context of SIV/HIV infection.

Sujets

• SIV
• T cell
• Apoptosis
• FAS
• Lymphocyte T suppresseur

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 6
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Garibal et al. Virology Journal 2012, 9 :220 http://www.virologyj.com/content/9/1/220

R E S E A R C H Open Access IL-2 immunotherapy in chronically SIV-infected Rhesus Macaques Julie Garibal 1 , Mireille Laforge 4 , Ricardo Silvestre 6 , Shahul Mouhamad 1 , Laure Campillo-Gimenez 1 , Yves Lévy 1,2,3* and Jérôme Estaquier 1,5*

Abstract Background: Despite inducing a sustained increase in CD4+ T cell counts, intermittent recombinant IL-2 (rIL-2) therapy did not confer a better clinical outcome in HIV-infected patients enrolled in large phase III clinical trials ESPRIT and SILCAAT. Several hypotheses were evoked to explain these discrepancies. Here, we investigated the impact of low and high doses of IL-2 in Rhesus macaques of Chinese origin infected with SIVmac251 in the absence of antiretroviral therapy (ART). Results: We demonstrated that rIL-2 induced a dose dependent expansion of CD4+ and CD8+ T cells without affecting viral load. rIL-2 increased CD4 and CD8 Treg cells as defined by the expression of CD25 high FoxP3 + CD127 low . We also showed that rIL-2 modulated spontaneous and Fas-mediated CD4 + and CD8 + T cell apoptosis. The higher dose exhibited a dramatic pro-apoptotic effect on both CD4 + and CD8 + T cell populations. Finally, all the animals treated with rIL-2 developed a wasting syndrome in the month following treatment simultaneously to a dramatic decrease of circulating effector T cells. Conclusion: These data contribute to the understanding of the homeostatic and dosage effects of IL-2 in the context of SIV/HIV infection. Keywords: SIV, IL-2 immunotherapy, T cells, Apoptosis, Fas, Treg

Background dysregulation and, in addition, implies risk of drug re- Progressive decrease in the number of CD4 + T lympho- sistance and long terms toxicity [2,3]. This has led to cytes is the hallmark of HIV (Human Immunodeficiency evaluate therapeutic strategies that could reinforce Virus) or SIV (Simian Immunodeficiency Virus) infec- HAART effect or even delay the initiation of antiretro- tion. During this chronic infection, CD4 + T cell loss, viral treatment. The best studied of these therapeutic generalized immune activation and increased susceptibil- approaches is intermittent administration of interleukin- ity to apoptosis result in impaired T cell homeostasis 2 (IL-2). and subsequent development of opportunistic infections IL-2 is an autocrine T cell growth factor mainly pro- [1]. Mechanisms leading to CD4 + T cell depletion are duced by activated T cells and implicated in the homeo- not completely understood yet but viral replication plays stasis and differentiation of Th1, Th2, Th17 and a key role in this process. Highly Active Antiretroviral regulatory T cell subsets. In HIV infection, due to pro- therapy (HAART), by allowing virological suppression, gressive loss of CD4 + T cells, levels of IL-2 are reduced. significant rise in CD4 + T cell counts and decrease in This progressive decrease of IL-2 producing CD4 + T apoptosis sensitivity, has dramatically improved clinical cells has been directly correlated with activation state outcome for HIV patients. However, this treatment par- and susceptibility to apoptosis of these cells [4-7]. More- tially fails to normalize HIV/SIV-associated immune over, IL-2 was found to improve survival of HIV patients ’ T cells ex vivo through the upregulation of the * Correspondence: [e-mail] ; [e-mail] anti-apoptotic protein Bcl-2 [8-10]. Partial restoration of 1 INSERM U955 Equipe 16, Institut Mondor de Recherche Biomédicale, erved fol n 5 Cr U é n t i e v il e F r - si 9 té 40 L 1 a 0 v , a F l, ra C n e c n e trederechercheenInfectiologie,Québec,Canada IL-2produci it n h g H CD A 4 A + RT Tc [1 el 1 l ]. po O o n li t s he ob o s therhand l , ow I i L-2 g treatment w Full list of author information is available at the end of the article has also been shown to play a key role in pro-apoptotic © 2012 Garibal et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.