Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques

Abstract

Interferon-␣ (IFN-␣)-based therapy ispresently the standard treatment for hepatitis C virus (HCV)-infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus-infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-␣-induced lymphopenia. We showed that low-dose IFN-␣ treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high-dose IFN-␣ treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-␣. Indeed, the association of both cytokines resulted in increased circulating T-cell IntroductionCoinfection with HIV and hepatitis C virus (HCV) has become an increasingly common occurrence, with an estimated 25% to 30% of HIV ϩ patients also being HCV ϩ . 1 As a consequence, since the appearance of highly active antiretroviral therapy (HAART), chronic liver disease has become one of the most common causes of morbidity and mortality in HIV patients. 2,3 Although the effectiveness of standard HCV treatment, based on interferon-␣ (IFN-␣) injections, is known to decrease the longer a patient has been infected with the virus, HCV patients are not systematically put under treatment. Rather, initiation of treatment depends on the state of the patient's liver (fibrosis markers, serum aminotransferases, HCV RNA, hepatitis B virus status) and other parameters, which in turn are used to determine whether the potential benefits of therapy outweigh the risks of treatment-related toxicity. 4 For HIV-HCV-coinfected patients, some of these parameters are: the assessment of HIV disease status, such as current and past opportunistic infections, HIV-associated malignancies, CD4 count, HIV viral load, and details of HAART therapy, with CD4 count being one of the main criteria. Unfortunately, coinfected patients are poor responders to standard treatment as a sustained viral response occurs in only 27% to 40% of these patients, approximately half the rate seen in HCV-monoinfected patients. [5][6][7] The main reason for this difference can be attributed to exhaustion of the immune system. In addition, IFN-␣ treatment causes a leukopenia, including a decrease of lymphocyte numbers and thus of CD4 count, often leading to premature treatment interruption. [8][9][10][11][12] Therefore, to enhance the efficiency of anti-HVC therapy in coinfected patients, it is critically important to develop an alternative treatment that limits the lymphopenic effect of IFN-␣ therapy.Interleukin 7 (IL-7), a cytokine that promotes precursor B-and T-cell maturation [13][14][15] and supports peripheral T-cell homeostasis, [16][17][18...

CD127 Expression, Exhaustion Status and Antigen Specific Proliferation Predict Sustained Virologic Response to IFN in HCV/HIV Co-Infected Individuals

“…The use of adjuvants such as IL-7 [69] that may counteract some of the lymphopenic effects of IFN-α may sustain functionality of CD4 and CD8 T cells and improve treatment efficacy. We have shown in this study that baseline levels of CD127 expression and antigen specific proliferation may together provide good predictors of the response to therapy.…”

Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing

“…Peripheral blood cell phenotype was analyzed from frozen whole blood by flow cytometry using a BD FACS CANTO II (BD Biosciences, Le Pont de Claix, France) as described (41). The fluorochrome-conjugated antibodies used for polycromatic flow cytometric analysis are listed in Table S3 in Supplementary Material.…”

Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival

“…Alpdogan et al [56] demonstrated the immune reconstitution effects of IL-7 administration in a mouse model of allogeneic HSCT and Storek et al did the same in a baboon model of autologous transplant [57]. This impressive immune reconstitution potential is also well documented in three reports on SIV-infected monkeys [58–60] and has more recently been shown to counteract interferon-induced lymphopenia [61]. In all these models, reconstitution involves both CD4 and CD8 lymphocytes as well as naïve and memory T cells.…”

“…The cytokine lead to an upregulation of homing chemokine receptors on T cells including CXCR4, CCR6, and CCR9 coupled with increased chemokine levels in tissues (CCL19, CCL20, CCL21, and CCL25) and plasma (CCL3, CCL4, and CXCL12). The teams of Li et al and Pellegrini et al, elegantly demonstrated that IL-7 treatment of mice induces a massive T cell infiltration in murine tumor leading to an enhanced anti-tumor protection correlated with an increased number of activated dendritic cells [61, 62]. Moreover, IL-7 will decrease the immunosuppressive environment in the tumor by decreasing TGFbeta secretion a key cytokine for immunosuppressive Treg.…”