HTLV-I REPLICATION AND CELL-SIGNALING PATHWAY MODULATION

HTLV-I 复制和细胞信号传导途径调节

• 批准号: 3085490
• 负责人: DEBORAH J GUYOT
• 金额: $ 7.84万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-15 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3085490
• 关键词: CD2 molecule; CD3 molecule; CD4 molecule; CD8 molecule; T lymphocyte; antireceptor antibody; biological signal transduction; calcium flux; cyclic AMP; human T cell lymphotropic virus type 1; human tissue; latent virus infection; lymphocyte proliferation; protein kinase C; receptor expression; tissue /cell culture; virus DNA; virus RNA; virus antigen; virus replication

Human T Lymphotropic Virus Type 1 (HTLV-I) was the first human retrovirus discovered. Infection is endemic in parts of the United States, Japan and the tropics and it is considered the etiologic agent of two disease syndromes, an aggressive adult T cell leukemia and an immune-mediated chronic progressive myelopathy. An estimated 1-4% of infected individuals will develop HTLV-I-related discase, often decades after the initial infection. The immunopathogenic mechanism by which the virus is released from its latent state and induces cellular transformation is not understood. We hypothesize that signal transduction initiated via normal cell-signaling pathways, the TCR/CD3 complex and the CD2 receptor promotes viral replication and leukemogenesis. The HTLV-I long terminal repeat contains sequences responsive to both cyclic adenosine monophosphate (CANT) and protein kinase C (PKC). It is postulated that differential stimulation of these second messenger systems may co-regulate viral expression and cellular activation or transformation. To investigate this hypothesis I intend to manipulate protein kinase pathways using CAMP and PKC analogues and inhibitors in HTLV-I infected peripheral blood lymphocytes. This will be followed by receptor-mediated activation using monoclonal antibodies to cluster determinants (CD2, CD3, CD4 and CD8). Viral expression and cellular activation will be evaluated using complementary techniques to identify soluble and cell-associated viral antigens, HTLV-I mRNA and proviral DNA; intracellular calcium flux, phenotypic expression of membrane receptors and cell proliferation. It is anticipated that such manipulations will help clarify mechanisms of latency and cellular transformation associated with HTLV-I infection.

人类T淋巴病毒1型（HTLV-I）是第一个人逆转录病毒 发现。 在美国，日本和 热带地区被认为是两种疾病的病因学药 综合征，一种侵略性的成人T细胞白血病和免疫介导的 慢性进步性骨髓病。 估计有1-4％的感染者 最初几十年后，将开发与HTLV-1相关的静态 感染。 病毒释放的免疫发育机制 从其潜在状态并诱导细胞转化是 理解。 我们假设通过正常发起的信号转导 细胞信号途径，TCR/CD3复合物和CD2受体促进 病毒复制和白血病。 HTLV-I长时重复 包含对两个环状腺苷单磷酸（CAN）的序列 和蛋白激酶C（PKC）。 据推测，差异刺激 这些第二信使系统可能会共同调节病毒表达和 细胞激活或转化。 研究这一假设I 打算使用CAMP和PKC类似物操纵蛋白激酶途径 HTLV-1感染的外周血淋巴细胞中的抑制剂。 这会 然后使用单克隆抗体的受体介导的激活 集群决定簇（CD2，CD3，CD4和CD8）。 病毒表达和 将使用互补技术评估细胞激活 鉴定可溶性和与细胞相关的病毒抗原，HTLV-I mRNA和 病毒DNA；细胞内钙通量，膜的表型表达 受体和细胞增殖。 预计这样的 操作将有助于阐明潜伏期和细胞的机制 与HTLV-I感染相关的转化。