Role of IL-7 in Human Immunodeficiency Virus Infection

IL-7 在人类免疫缺陷病毒感染中的作用

• 批准号: 8555906
• 负责人: paolo lusso
• 金额: $ 35.9万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8555906
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adolescent; Adverse effects; Aftercare; Animals; Anti-Retroviral Agents; Apoptosis; Apoptotic; Attention; Autologous; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Cycle; Cell Proliferation; Cells; Chronic; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Dose; Event; Experimental Designs; Fostering; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Home environment; Homing; Immune; Immune response; Immunologics; Individual; Infection; Injection of therapeutic agent; Integrins; Interleukin 7 Receptor; Interleukin-7; Interruption; Intestines; Investigation; Ionomycin; Kinetics; Ligands; Link; Lymphoid Tissue; Lymphopenia; Macaca; Macaca mulatta; Malignant Neoplasms; Mediating; Memory; Modeling; Molecular; Monitor; Mus; Pathogenesis; Pathway interactions; Patients; Peripheral; Phase; Phenotype; Phorbol Esters; Physiological; Placebos; Plasma; Play; Predisposition; Process; Proliferating; Proteins; Protocols documentation; Recombinants; Research; Role; SIV; Signal Pathway; Site; Staging; Structure of aggregated lymphoid follicle of small intestine; T cell response; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFRSF6 gene; Testing; Time; Tissues; Up-Regulation; Validation; Viremia; Virus Diseases; Virus Replication; chemokine receptor; cytokine; in vivo; in vivo Model; lymph nodes; memory CD4 T lymphocyte; model design; nonhuman primate; programs; reconstitution; research clinical testing; research study; response

IL-7 is currently under clinical investigation as a potential immune-reconstitution agent for various forms of immuno-deficiency, including HIV infection and cancer. However, its effects have never been evaluated during acute HIV-1 (or SIV) infection, a critical phase of the disease in which the most dramatic depletion of CD4(+) T cells is believed to occur. To investigate the effects of IL-7 in an in vivo model of HIV-1 infection, we performed a study of IL-7 treatment during the acute phase of SIV infection in a well-established nonhuman primate model of AIDS. Our study included 12 juvenile rhesus macaques divided into two groups: Group 1 (n=6) was infected with a pathogenic SIV isolate, SIVmac251, and received weekly injections of placebo; group 2 (n=6) was infected with SIV and concomitantly treated with fully glycosylated recombinant macaque IL-7 s.c., once per week for 7 weeks, at a dose of 50 ug/kg. They received no antiretroviral treatment. Multiple clinical, immunological and virological parameters were monitored in all study animals throughout the acute phase of SIV infection. Treatment with IL-7 did not cause clinically detectable side effects and, despite the absence of concomitant ART, did not induce significant increases in the levels of SIV replication except at the earliest time point tested (day 4 post-infection). Strikingly, animals treated with IL-7 were protected from the dramatic decline of circulating nave and memory CD4(+) T cells that occurred in untreated animals. Treatment with IL-7 induced only transient T-cell proliferation, but it was associated with sustained increase in the expression of the anti-apoptotic protein Bcl-2 on both CD4(+) and CD8(+) T cells, persistent expansion of all circulating CD8(+) T-cell subsets, and development of earlier and stronger SIV Tat-specific T-cell responses. However, the beneficial effects of IL-7 were not sustained after treatment interruption. These data demonstrate that IL-7 administration is effective in protecting the CD4(+) T-cell pool during the acute phase of SIV infection in macaques, providing a rationale for the clinical evaluation of this cytokine in patients with acute HIV-1 infection. Next, we focused our attention on the role of IL-7 in T-cell peripheral homing. Increasing attention is being focused on the gut-associated lymphoid tissue (GALT) as a major target tissue for HIV infection, where critical events for pathogenesis take place. Specifically, the GALT is a primary anatomical site for virus replication, particularly during the early stages of HIV infection, leading to extensive depletion of CD4+ T cells. Since IL-7 plays an important role in peripheral T-cell homing, we investigated the ex vivo effects of exogenous IL-7 on the expression of a large panel of tissue-homing integrins and chemokine receptors. We observed that IL-7, in the absence of any concomitant stimulation, potently and selectively induces the expression of the principal gut-homing integrin, a4b7, in both CD4+ and CD8+ T cells. We found that this effect: i) is specific for T cells; ii) is rapidly induced upon IL-7 treatment; iii) requires supra-homeostatic concentrations of IL-7 (those typically reached under conditions of lymphopenia); iv) is uncoupled from the expression of classic markers of cellular activation; and v) is associated with the functional activation of the integrin, as indicated by an increased binding activity for its natural ligand, MAdCAM. Investigation of the molecular mechanisms of a4b7 induction by IL-7 revealed the involvement of both major signaling pathways linked to stimulation of the IL-7 receptor, i.e., the JAK/STAT and PI3K/Akt pathways. Induction of a4b7 by IL-7 was also confirmed in vivo, both in HIV-infected subjects and in SIV-infected macaques treated with IL-7. Of note, we found that induction of a4b7 by IL-7 occurs predominantly in phenotypically nave T cells, which concomitantly acquire a memory-like phenotype, as shown by upregulation of CD95 expression and secretion of TNF-a; upon stimulation with phorbol esters and ionomycin, despite an unaltered expression of CD45RA and CD45RO. This memory-like masquerade is similar to that previously documented in vivo in nave T cells of mice recovering from lymphopenia. Nave T cells were also induced to proliferate by IL-7, in the absence of any concomitant stimulation, albeit with delayed kinetics compared to a4b7 induction. These results are compatible with a new model of host response to lymphopenia whereby supra-homeostatic levels of IL-7 activate an unusual program of phenotypic modulation in nave T cells, characterized by the acquisition of a gut-homing and memory-like phenotype prior to the induction of cell cycling and proliferation. The role of intestinal T-cell homing in the reconstitution of the depleted T-cell pool in lymphopenic hosts remains to be defined. To formally demonstrate the physiological relevance of a4b7 induction by IL-7, we performed an in vivo study in which humanized NSG mice were injected with autologous T cells treated or not with IL-7. The results of these experiments clearly documented a preferential intestinal homing of IL-7-treated naive T cells, while no preferential homing to other tissues was detected. The physiological relevance of these phenomena in the processes of immunologic reconstitution is currently under investigation. During the course of HIV-1 infection, the endogenous levels of IL-7 naturally increase to supra-homeostatic concentrations in response to lymphopenia during the progression of the disease. Thus, we hypothesized that the ability of IL-7 to redirect naive T cells to the intestinal compartment could occur in vivo in individuals with progressive HIV-1 disease. To investigate these phenomena and their relevance to AIDS in an in vivo model, we designed a new study in which 6 macaques chronically infected with either SIVmac251 or SIVsmE543 received a single injection of IL-7 (50 ug/kg, s.c.) and were sacrificed seven days later in order to specifically investigate the effects of IL-7 on T-cell homing and SIV replication in peripheral lymphoid tissues, particularly the GALT; three chronically SIV-infected animals received placebo and served as untreated controls. Detailed phenotypic analysis of circulating T cells documented a rapid upregulation of a4b7 in both CD4+ and CD8+ T cells. Comparison of pre-treatment and post-treatment intestinal tissues demonstrated that IL-7 administration resulted in increased numbers of infiltrating T cells within the GALT, associated with increased levels of SIV replication, predominantly in the Peyers patches. Enhanced SIV replication was also detected in lymph nodes. The increased levels of SIV replication in peripheral lymphoid tissues were mirrored by consistent increases in SIV plasma viremia. These in vivo data provide an initial validation of our hypothesis that the surge of endogenous IL-7 that occurs during the late stages of HIV infection may foster the terminal depletion of the CD4+ T-cell pool through the induction and activation of a4b7 leading to increased intestinal homing and HIV susceptibility.

IL-7目前正在临床研究中，作为一种潜在的免疫重建剂，用于治疗各种形式的免疫缺陷，包括HIV感染和癌症。然而，在急性HIV-1（或SIV）感染期间，它的作用从未被评估过，这是该疾病的关键阶段，CD4(+) T细胞耗竭被认为是最显著的。为了研究IL-7在体内HIV-1感染模型中的作用，我们在一个成熟的非人类灵长类艾滋病模型中研究了IL-7在SIV感染急性期的治疗。我们的研究包括12只幼年恒河猴，分为两组：第一组（n=6）感染致病性SIV分离物SIVmac251，每周注射安慰剂；第2组（n=6）感染SIV并同时给予完全糖基化重组猕猴IL-7 s.c，每周1次，剂量为50 ug/kg，共7周。他们没有接受抗逆转录病毒治疗。在SIV感染的整个急性期，对所有研究动物的多项临床、免疫学和病毒学参数进行了监测。用IL-7治疗没有引起临床可检测到的副作用，尽管没有伴随ART，但除了在测试的最早时间点（感染后第4天）外，没有引起SIV复制水平的显着增加。引人注目的是，用IL-7治疗的动物不像未经治疗的动物那样出现循环中性和记忆CD4(+) T细胞的急剧下降。IL-7治疗仅诱导短暂的T细胞增殖，但它与CD4（+）和CD8(+) T细胞上抗凋亡蛋白Bcl-2表达的持续增加、所有循环CD8(+) T细胞亚群的持续扩增以及更早和更强的SIV tat特异性T细胞反应的发展有关。然而，IL-7的有益作用在治疗中断后并没有持续。这些数据表明，在猴SIV感染急性期，给药IL-7可有效保护CD4(+) t细胞池，为临床评估该细胞因子在急性HIV-1感染患者中的作用提供了依据。