IL-15 treatment of SIV-infected non-human primates

IL-15 治疗 SIV 感染的非人灵长类动物

• 批准号: 7149982
• 负责人: PETER D KATSIKIS
• 金额: $ 55.54万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149982
• 关键词: Affect; Animals; Antiviral Agents; Apoptosis; Apoptotic; CD8B1 gene; Cell Count; Cells; Cessation of life; Chronic; Data; Defect; Exhibits; Goals; HIV; HIV Infections; Immune response; Immunity; In Vitro; Infection; Interleukin-15; Macaca; Macaca mulatta; Mediating; Memory; Mus; Natural Killer Cells; Numbers; Patients; Phenotype; Pilot Projects; Play; Predisposition; Production; Proliferating; Property; Recombinants; Research; Role; SELL gene; SIV; Staging; T-Lymphocyte; Therapeutic; Therapeutic Uses; Time; Viral Load result; Virus Diseases; base; cell killing; cytokine; cytotoxic; cytotoxicity; design; human study; in vivo; killings; macrophage; nonhuman primate; novel; novel therapeutics; novel vaccines; peripheral blood; response

Cytotoxic CD8+ T cell (CTL) responses play a critical protective role against HIV virus. A number of studies, however, have indicated that HIV-specific CD8+ T cells may be functionally impaired. Furthermore, we have demonstrated that HIV-specific CD8+ T cells exhibit increased susceptibility to undergo CD95/Fas-mediated apoptosis and HIV-infected macrophages can kill these cells. This apoptosis of HIV-specific CD8+ T cells therefore may impair their ability to function as serial killers. Augmenting the effector function and the survival of HIV-specific CD8+ T cells would greatly enhance the efficiency of these cells to control or clear HIV virus. Interleukin 15 (IL-15) is a pluripotent cytokine that we have shown potently inhibits CD95/Fas-mediated apoptosis of HIV-specific CD8+ T cells and upregulates the anti-apoptotic Bcl-2 and Bcl-xL molecules in these cells. Furthermore IL-15 enhances their cytotoxic activity and IFNgamma production. SIV-specific CD8+ T cells from SIV-infected rhesus macaques also show increased sensitivity to CD95/Fas-mediated apoptosis and IL-15 potently inhibits this apoptosis and upregulates Bcl-2 and Bcl-xL molecules. Based on these observations, we recently performed a short pilot study in chronically SIV-infected cynomolgus macaques to investigate the potentially beneficial effect of IL-15 treatment in vivo. In vivo treatment with IL-15 significantly increased peripheral blood CD8-t- T cell and NK cell numbers by more than 2-fold. This increase was mainly due to proliferation of CD8+ T cells, as proliferating Ki67^ CD8+ T cells increased with treatment. The expanded CD8+ T cells were of the CD45RA- CD62L- and CD45RA+ CD62L- effector memory phenotype. We hypothesize that IL-15 treatment in vivo can enhance cytotoxic CD8+ T cells immunity against SIV and enhance antiviral immunity. We propose to examine the effect of in vivo treatment with recombinant simian IL-15 on primary and chronic SIV infection of rhesus macaques. Synergy with ART treatment will also be evaluated in chronic infection studies. Viral load, immunological changes, apoptosis and Bcl-2/Bcl-xL molecule expression will be evaluated. In particular the effect of in vivo IL-15 treatment on SIV-specific CTL response will be investigated. The studies in this proposal are novel and will provide valuable information on the potential therapeutic value of IL-15. Information yielded from these studies may prove useful for the design of novel therapeutic strategies against HIV infection and other viral infections.

细胞毒性CD8+ T细胞（CTL）反应起着针对HIV病毒的关键保护作用。然而，许多研究表明，HIV特异性CD8+ T细胞在功能上可能受损。此外，我们已经证明，HIV特异性的CD8+ T细胞表现出增加对发生CD95/FAS介导的细胞凋亡的敏感性，并且感染了HIV的巨噬细胞可以杀死这些细胞。因此，这种HIV特异性CD8+ T细胞的凋亡可能会损害其充当连环杀手的能力。增强效应子功能和HIV特异性CD8+ T细胞的存活将大大提高这些细胞控制或清除HIV病毒的效率。白介素15（IL-15）是一种多能细胞因子，我们显示出强有力地抑制HIV特异性CD8+ T细胞的CD95/FAS介导的凋亡，并上调抗凋亡BCL-2和BCL-XL分子在这些细胞中。此外，IL-15增强了其细胞毒性活性和IFNGAMMA的产生。来自SIV感染的恒河猕猴的SIV特异性CD8+ T细胞还显示出对CD95/FAS介导的凋亡的敏感性增加，IL-15有效抑制了这种凋亡，并上调了Bcl-2和Bcl-XL分子。基于这些观察结果，我们最近在慢性SIV感染的Cynomolgus猕猴中进行了一项简短的试点研究，以研究体内IL-15治疗的潜在有益作用。在体内用IL-15处理显着增加了外周血CD8-T-T细胞和NK细胞数量超过2倍。这种增加主要是由于CD8+ T细胞的增殖，因为随着治疗的增殖而增殖的Ki67^ CD8+ T细胞增加。扩展的CD8+ T细胞是CD45RA-CD62L-和CD45RA+ CD62L-效应的记忆表型。我们假设体内IL-15治疗可以增强对SIV的细胞毒性CD8+ T细胞免疫力并增强抗病毒药性。我们建议检查体内重组Simian IL-15对猕猴的原发性和慢性SIV感染的影响。在慢性感染研究中还将评估与艺术治疗的协同作用。将评估病毒载量，免疫变化，凋亡和BCL-2/BCL-XL分子表达。特别是，将研究体内IL-15治疗对SIV特异性CTL反应的影响。该提案中的研究是新颖的，将提供有关IL-15潜在治疗价值的有价值信息。这些研究产生的信息可能被证明可用于设计针对HIV感染和其他病毒感染的新型治疗策略。