Anti-HIV-1 Effect of TALL-104 Cells

描述(申请人提供)：基于免疫的治疗方法，通过激活MHC限制性机制，如CD8+T细胞效应器功能，直接抑制病毒复制，仍然是一个积极的研究领域。在这里，我们建议研究一种基于MHC非限制性人类细胞毒T细胞株TALL-104(CD3/TCR+CD8+CD56+CD16-)的抗病毒活性的新方法。TALL-104细胞在体外对几个物种的广泛肿瘤具有细胞毒作用，而不溶解正常组织中的细胞。重要的是，TALL-104细胞已经在临床前研究(超过10年)中被广泛描述为一种过继细胞疗法，包括FDA批准的用于治疗癌症患者的I/II期人类临床试验。我们在HIV感染培养中的初步数据显示，TALL-104细胞在体外可以抑制病毒复制并杀死HIV感染细胞。TALL-104介导的对慢性感染的ACH-1和U1细胞的杀伤增加与这些细胞中的HIV复制有关。基于更多关于慢性感染T细胞病毒抑制的初步数据，我们建议检验TALL-104细胞可以通过激活非MCH限制性机制(包括直接细胞毒作用和抗病毒可溶性因子的分泌)来抑制原代淋巴细胞和巨噬细胞中的HIV-1的假设。为了检验我们的假设，我们将评估： 1.分析原代细胞中TALL-104细胞的抗病毒活性，更具体地说： A)TALL-104细胞在急性感染X4和R5原代CD8缺失的T细胞和单核细胞来源的巨噬细胞(MDM)中抑制病毒复制的活性。 B)TALL-104细胞在HIV-1感染患者细胞中抑制激活诱导的病毒复制的能力。 2.通过以下方式确定TALL-104细胞抗HIV活性的机制： A)分析激活细胞毒性受体(NCR)NKp46和NKG2D在触发对艾滋病毒感染者的杀戮中的作用。 2)分析杀伤HIV感染细胞的细胞毒机制：细胞毒因子(颗粒酶和穿孔素)和细胞毒介质(Fas-L和肿瘤坏死因子相关的凋亡诱导配体-TRAIL)。 C)确定潜在的可溶性因子在抑制病毒复制中的作用(RANTES、MIP-1α、MIP-1β和SDF-1)。 建议的工作代表了维斯塔尔研究所、宾夕法尼亚大学、费城Fight(乔纳森·拉克斯治疗中心)之间的合作。

DESCRIPTION (provided by applicant): Immune-based therapy approaches that directly inhibit viral replication through activation of MHC-restricted mechanisms such as CD8+T cell effector function remain an area of active investigation. Here we propose to investigate a novel approach based on antiviral activity of a MHC non-restricted human cytotoxic T cell line, TALL-104 (CD3/TCR+ CD8+ CD56+ CD16-). TALL-104 cells are cytotoxic in vitro against a broad range of tumors across several species, without lysing cells from normal tissues. Importantly, TALL-104 cells have already been extensively characterized as an adoptive cell therapy in pre-clinical studies (over 10 years) including FDA approved phase I/II human clinical trials for the treatment of cancer patients. Our preliminary data in HIV-infected cultures show that TALL-104 cells can inhibit viral replication and kill HIV-infected cell in vitro. An increase in TALL-104 mediated killing of chronically infected lines ACH-1 and U1 was associated with HIV replication in these cells. Based on additional preliminary data documenting viral suppression of chronically infected T cells, we propose to test the hypothesis that TALL-104 cells can inhibit HIV-1 in primary lymphocytes and macrophages through activation of non-MCH-restricted mechanisms including direct cytotoxicity and secretion of antiviral soluble factors. In order to test our hypothesis, we will evaluate: 1. Analyze the antiviral activity of TALL-104 cells in primary cells, and more specifically: a) The activity of TALL-104 cells in decreasing viral replication in in vitro acutely infected X4 and R5 primary CD8-depleted T cells and monocyte-derived macrophages (MDM). b) The ability of TALL-104 cells to inhibit activation-induced viral replication in cells from HIV-1 infected patients. 2. Define the mechanisms involved in the anti-HIV activity by TALL-104 cells by: a) Analysis of the role of activating cytotoxic receptors (NCRs) NKp46 and NKG2D involved in triggering the killing HIV-infected. b) Analyzing the cytotoxic mechanisms responsible for killing HIV-infected cells: cytotoxic factors (granzymes and perforin) and cytotoxic mediators (Fas-L and tumor necrosis factor-related apoptosis-inducing ligand-TRAIL). c) Defining the role of potential soluble factors in the inhibition of viral replication (RANTES, MIP-1alpha, MIP-1beta and SDF-1). The work proposed represents a collaboration between The Wistar Institute, The University of Pennsylvania, Philadelphia FIGHT (Jonathan Lax Treatment Center).