Immunomodulatory Function of Human T Cell Leukemia Virus Type 2 (HTLV-2)

人 T 细胞白血病病毒 2 型 (HTLV-2) 的免疫调节功能

• 批准号: 8259061
• 负责人: MARK A BEILKE
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259061
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adult; Affect; Antigens; Antiviral Agents; Binding; Blood donor; CCR5 gene; CD4 Positive T Lymphocytes; CD8B1 gene; CREB1 gene; Caring; Cell Survival; Cells; Clinical; Computerized Medical Record; Data; Disease; Down-Regulation; Enrollment; Epidemic; Escherichia coli; Exhibits; Genes; Genetic; Goals; HIV; HIV therapy; HIV-1; Health; Healthcare; Healthcare Systems; Highly Active Antiretroviral Therapy; Human; Human T-Cell Leukemia Viruses; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; Immune; Immune response; Immunology; Immunomodulators; In Vitro; Individual; Infection; Italy; Jurkat Cells; Laboratories; Life Cycle Stages; Lymphocyte; Lymphocyte Count; Lymphocyte Function; Lymphoid Cell; Mediating; NF-kappa B; Natural Killer Cells; Neurodegenerative Disorders; Nuclear; Oncogene Proteins; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Plasma; Production; Proteins; RNA; Receptor Down-Regulation; Recombinants; Registries; Relative (related person); Reporting; Research; Retroviridae; Role; Spastic; Spinal Cord Diseases; System; T-Cell Leukemia; T-Lymphocyte Subsets; Time; Toxic effect; Transactivation; Treatment Failure; Veterans; Viral; Virus; Work; base; beta-Chemokines; chemokine; chemokine receptor; genetic regulatory protein; health care service utilization; improved; in vitro activity; indexing; leukemia virus; leukemia/lymphoma; mutant; novel strategies; pathogen; promoter; receptor expression; research study

DESCRIPTION (provided by applicant) The human T leukemia virus type 1 (HTLV-1) and its genetic counterpart, HTLV-2, are the first-described human retroviruses. Unlike human immunodeficiency virus (HIV-1), infections with HTLV-1 and HTLV-2 are generally silent and asymptomatic for the entire lifetime of an individual. The differential pathology seen between HIV-1 and HTLV-1 and HTLV-2 is most likely attributable to differences in viral accessory genes regulating viral replication, latency, and transport within the host cell. In the case of HTLV-1 and HTLV-2, the transcriptional activating proteins, known as Tax1 and Tax2, are essential for viral replication, but are also cellular promoters via the CREB and NF:B pathways. The in vitro activity of the HTLV-1 Tax1 protein has been evaluated extensively, especially in the context of its ability to function as an oncoprotein. Tax2 seems to lack this ability, which may account in part for the low pathogenecity of HTLV-2. Tax2 has additionally been reported to exhibit poor transactivation of both CREB and NF:B. Nonetheless, preliminary experiments conducted in our laboratory indicate that Tax2 protein expressed in E. coli (or in stably transduced Jurkat cells) is a potent inducer of beta chemokines by peripheral blood mononuclear cells (PBMCs), and was observed to down-regulate CCR5 co-receptor expression and improve PBMC viability and lymphoproliferative capacity. Additionally, Tax2 was shown to inhibit HIV-1 p24 antigen release in HIV-1 infected PBMCs and lymphoid cells. Hypothesis: HTLV-2 and its regulatory gene product, Tax2, have the potential to modify innate host immune responses though increased lymphocyte viability and proliferation, induction of beta chemokines, and down-regulation of CC-chemokine receptors. The resultant effects could alter host responses during co- infection with other pathogens, including HIV-1. Specific Aims: (1) To confirm and validate the in vitro function of Tax2, wild type HTLV-2 (wtHTLV-2) will be compared with a Tax2-deficient HTLV-2 infectious clone ( TaxHTLV-2) with respect to their ability to affect PBMC proliferative capacity and elaboration of the beta chemokines. As a subaim, relative levels of beta chemokine expression in CD4+ vs. CD8+ T cell subsets will be compared. (2) To determine a mechanism of Tax2-mediated-induction of antiviral chemokines by comparing the ability of a recombinant Tax2 protein with a panel of Tax2 mutants. Mutant proteins will include alterations in the NF-KB activating region, CREB binding region, and nuclear localization region. (3) To implicate a possible dominant role of the HTLV-2 Tax2 protein as a possible immunomodulator during HIV-1/HTLV-2 co- infection. The overall goal of this research is to develop an understanding of the role of Tax2 in modulating lymphocyte function in HTLV-2 infected individuals, and to implicate its role in modifying HIV-1 infection in patients with HIV-1/HTLV-2 co-infections. The project explores a novel approach of examining the potential of an accessory protein of one virus (HTLV-2) to alter the biologic life cycle of a second, related virus (HIV-1) in the host cell reservoirs. We expect that the proposed research will advance our understanding of the dynamics of retroviral infections which affect thousands of Veteran's nationwide. PUBLIC HEALTH RELEVANCE: Relevance of the proposed research to veterans health and/or healthcare issues: The HIV epidemic has had a major impact on the VA healthcare system [http://www.hiv.va.gov/vahiv?page=prin-data-2005]. Since 1998, the VA has tracked the care provided to patients with HIV disease through the Immunology Case Registry (ICR). Data for the ICR are drawn from the VA's electronic medical record system, which includes a broad range of information on clinical condition and health care utilization. There were an estimated of 26,000 HIV infected veterans enrolled at VA facilities for treatment during FY2005. Many HIV infected veterans are reluctant to adhere to HAART therapy because of concerns related to toxicity. For these reasons, any new strategies for therapy associated with lower rates of toxicity and treatment failure are critically needed for HIV infected individuals. The proposed studies will focus on exploring possible strategies for immune based therapy of HIV infected patients.

描述（由申请人提供） 人类 T 白血病病毒 1 型 (HTLV-1) 及其基因对应物 HTLV-2 是首次被描述的人类逆转录病毒。与人类免疫缺陷病毒 (HIV-1) 不同，HTLV-1 和 HTLV-2 的感染通常在个体的整个一生中都是沉默且无症状的。 HIV-1与HTLV-1和HTLV-2之间的不同病理学很可能归因于调节宿主细胞内病毒复制、潜伏和运输的病毒辅助基因的差异。就 HTLV-1 和 HTLV-2 而言，转录激活蛋白（称为 Tax1 和 Tax2）对于病毒复制至关重要，但也是通过 CREB ​​和 NF:B 途径的细胞启动子。 HTLV-1 Tax1 蛋白的体外活性已得到广泛评估，特别是在其作为癌蛋白发挥作用的能力方面。 Tax2 似乎缺乏这种能力，这可能是 HTLV-2 致病性低的部分原因。据报道，Tax2 对 CREB ​​和 NF:B 的反式激活也较差。尽管如此，我们实验室进行的初步实验表明，大肠杆菌（或稳定转导的 Jurkat 细胞）中表达的 Tax2 蛋白是外周血单核细胞 (PBMC) β 趋化因子的有效诱导剂，并观察到下调 CCR5 共受体表达并提高 PBMC 活力和淋巴增殖能力。此外，Tax2 可抑制 HIV-1 感染的 PBMC 和淋巴细胞中 HIV-1 p24 抗原的释放。假设：HTLV-2 及其调节基因产物 Tax2 有可能通过增加淋巴细胞活力和增殖、诱导 β 趋化因子以及下调 CC 趋化因子受体来改变宿主先天免疫反应。由此产生的影响可能会改变宿主在与其他病原体（包括 HIV-1）共感染期间的反应。具体目标： (1) 为了确认和验证 Tax2 的体外功能，将野生型 HTLV-2 (wtHTLV-2) 与 Tax2 缺陷型 HTLV-2 感染性克隆 (TaxHTLV-2) 进行比较，比较它们影响 PBMC 增殖能力和 β 趋化因子加工的能力。作为子目标，将比较 CD4+ 与 CD8+ T 细胞亚群中 β 趋化因子表达的相对水平。 (2)通过比较重组Tax2蛋白与一组Tax2突变体的能力来确定Tax2介导的抗病毒趋化因子的诱导机制。突变蛋白将包括 NF-KB 激活区、CREB ​​结合区和核定位区的改变。 (3)暗示HTLV-2 Tax2蛋白在HIV-1/HTLV-2共感染期间作为可能的免疫调节剂可能发挥主导作用。本研究的总体目标是了解 Tax2 在调节 HTLV-2 感染者淋巴细胞功能中的作用，并揭示其在改变 HIV-1/HTLV-2 合并感染患者的 HIV-1 感染中的作用。该项目探索了一种新方法，检查一种病毒的辅助蛋白 (HTLV-2) 改变宿主细胞库中另一种相关病毒 (HIV-1) 的生物生命周期的潜力。我们期望拟议的研究将增进我们对逆转录病毒感染动态的理解，逆转录病毒感染影响着全国数千名退伍军人。 公共卫生相关性： 拟议研究与退伍军人健康和/或医疗保健问题的相关性：艾滋病毒流行对 VA 医疗保健系统产生了重大影响 [http://www.hiv.va.gov/vahiv?page=prin-data-2005]。自 1998 年以来，退伍军人管理局通过免疫学病例登记处 (ICR) 跟踪为艾滋病毒患者提供的护理。 ICR 的数据取自 VA 的电子病历系统，其中包括有关临床状况和医疗保健利用的广泛信息。 2005 财年估计有 26,000 名感染艾滋病毒的退伍军人在退伍军人管理局机构登记接受治疗。由于担心毒性，许多感染艾滋病毒的退伍军人不愿意坚持HAART治疗。由于这些原因，HIV 感染者迫切需要任何与降低毒性和治疗失败率相关的新治疗策略。拟议的研究将重点探索艾滋病毒感染患者免疫治疗的可能策略。