Enhancing control of HIV by inhibiting TRAILshort

通过抑制 TRAILshort 加强对 HIV 的控制

• 批准号: 8698830
• 负责人: ANDREW D BADLEY
• 金额: $ 53.96万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-02 至 2015-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698830
• 关键词: Address; Adjuvant Therapy; Affect; Aftercare; Anti-Retroviral Agents; Antiviral Agents; Apoptosis; Berlin; Binding; Biological Assay; Biology; Bone Marrow Transplantation; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCR4 gene; Cause of Death; Cell Death; Cells; Cessation of life; Coculture Techniques; Cytotoxic Chemotherapy; Cytotoxic T-Lymphocytes; Data; Disease; Effector Cell; Fostering; Genetic; Goals; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Human; Immune; Immune response; Immune system; Immunologic Surveillance; Infection; Interferons; Interleukin-6; Intervention; Knock-out; Knowledge; Life; Life Cycle Stages; Ligands; Malignant Neoplasms; Measures; Mediating; Modeling; Myeloablative Chemotherapy; Names; Natural Killer Cells; Outcome; Pathogenesis; Patients; Persons; Production; Proteins; RNA Splicing; Regulation; Research; Research Proposals; Residual state; Resistance; Role; Signal Transduction; Stimulus; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; TNF gene; Testing; Tissues; Transplantation; Tumor Necrosis Factor-alpha; Variant; Viral; Viral Load result; Virus; Virus Diseases; Vorinostat; Work; Zinc Fingers; apoptosis inducing factor; arm; cancer cell; cell killing; cytotoxic; design; disease phenotype; gene therapy; humanized monoclonal antibodies; in vivo; interest; killings; macrophage; man; monocyte; novel; novel strategies; nuclease; prevent; purge; receptor; research study; response

DESCRIPTION (provided by applicant): The Berlin patient who has been effectively cured from HIV provides proof of concept for the feasibility of curing HIV infection from the human host. It is likely that at least four factors have contributed to HIV being cured in the Berlin patient: (i) prolonged and durable control of HIV infection prior to bone marrow transplant, (ii) cytotoxic chemotherapy killing the viral reservoir, (iii) being transplanted with CCR5 delta 32 cells which are resistant to infection, and (iv) a broadly effective immune response which was able to eradicate any residual infection. This case has spurred much scientific debate and speculation as to how to make cure of HIV a more generalizable and an achievable outcome. Given the potency of current antiretroviral agents, current efforts are focusing on developing novel ways of killing or purging the viral reservoir (eg SAHA), developing new approaches to generate cells which resist infection (eg Zinc finger nucleases for CCR5) and enhancing the immune control of HIV. TNF related apoptosis inducing factor (TRAIL) is a molecule whose principal function is as an effector of immune surveillance, and it has been implicated in the pathogenesis of both malignancies, as well as viral infections including HIV. Concerning the role of TRAIL in HIV, considerable evidence supports a role for TRAIL dysregulation occurring during HIV infection in vivo, and there is ample evidence that treatment of cells from HIV-infected patients on HAART with exogenous TRAIL, reduces the number of latently infected cells, as measured by undetectable levels of replication competent virus in quantitative co-culture assays. Since TRAIL is expressed by effector cells (i.e., CD8 and/or NK cells) of the immune system, we questioned why TRAIL-dependent natural immune mechanisms do not independently reduce the number of latently infected cells. We found that cells from HIV-infected patients produce a novel splice variant of TRAIL which we call TRAILshort, which antagonizes normal TRAIL signaling. We therefore propose a model whereby the production of TRAILshort by HIV-infected cells prevents these cells from being killed by either CTL or NK cells, and this allows a subset of infected cells to persist. The current research proposal concerns gaining understanding the biology of and developing ways to inhibit this TRAIL splice variant, which we have named TRAILshort (TRAILs). Since we have generated preliminary data which demonstrates that TRAILs blocks HIV induced killing of CD4 T cells, as well as killing induced by CTL and NK cells, we now propose to inhibit TRAILs as a means of increasing the rate at which HIV infected CD4 Tcells die, and thereby contributing to the goal of eradicating HIV infected cells, and a cure for HIV infection. In this regard, we have additional preliminary data indicating that inhibiting TRAILs achieves the goal of increasing killing of HIV infected T-cells, and enhancing both CTL and NK cell killing of target cells.

描述（由申请人提供）：柏林患者从HIV有效治愈的柏林患者提供了概念证明，以使人类宿主治愈HIV感染的可行性。至少有四个因素有助于在柏林患者中治愈HIV：（i）在骨髓移植前长时间且持久地控制HIV感染，（ii）细胞毒性化学疗法杀死病毒疗法，（病毒疗法），（III）（iii）用CCR5 Delta 32细胞具有易于启动的感染，并且（III）有效地（III III III III III III III II III III III） 感染。此案引发了许多科学辩论和猜测，即如何使HIV治愈成为更具普遍和可实现的结果。鉴于当前抗逆转录病毒药物的效力，当前的努力集中在开发杀死或清除病毒储层的新型方法（例如SAHA），开发出新的方法来产生抵抗感染的细胞（例如，用于CCR5的锌指核酸酶）并增强了HIV的免疫控制。 TNF相关的凋亡诱导因子（TRAIL）是一种分子，其主要功能是免疫监测的效应因子，并且与既有恶性肿瘤的发病机理以及包括HIV在内的病毒感染有关。与TRAIL在艾滋病毒中的作用相吻合，大量证据支持了体内艾滋病毒感染期间发生的跟踪失调的作用，并且有充分的证据表明，用外源性踪迹在HAART上对HIV感染的患者的细胞进行处理，从而减少了由未经定量的量化量子copultior量子量的可探测能力的型号，从而减少了潜在受感染的细胞的数量。由于TRAIL由免疫系统的效应细胞（即CD8和/或NK细胞）表达，因此我们质疑为什么跟踪依赖性的自然免疫机制不会独立减少潜在感染细胞的数量。我们发现，来自HIV感染患者的细胞会产生一种新型的TRAIL剪接变体，我们称之为Trailshort，它会拮抗正常的跟踪信号传导。因此，我们提出了一个模型，通过该模型，艾滋病毒感染细胞的Trailshort产生可防止这些细胞被CTL或NK细胞杀死，这允许感染细胞的子集持续存在。当前的研究建议涉及了解并开发抑制这种跟踪剪接变体的生物学的生物学，我们将其命名为Trailshort（Trails）。由于我们已经生成了初步数据，该数据表明，TRAIL会阻止HIV诱导的CD4 T细胞杀死以及由CTL和NK细胞诱导的杀死，因此我们现在建议抑制踪迹，以抑制HIV感染CD4 TCELL的速度，从而导致脱离HIV感染细胞的目标，从而抑制HIV感染细胞的靶向。在这方面，我们还有其他初步数据表明，抑制踪迹的目标是增加杀死HIV感染的T细胞的目标，并增强靶细胞的CTL和NK细胞杀死。