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（由申请方提供）：已有效治愈HIV的柏林患者为治愈人类宿主HIV感染的可行性提供了概念证明。可能至少有四个因素促成了柏林患者的HIV治愈：（i）骨髓移植前HIV感染的长期和持久控制，（ii）细胞毒性化疗杀死病毒库，（iii）移植了抗感染的CCR 5 δ 32细胞，以及（iv）广泛有效的免疫应答，能够根除任何残留感染。这一案例引发了许多科学辩论和猜测，如何使艾滋病毒的治愈成为一个更普遍和可实现的结果。鉴于目前抗逆转录病毒药物的效力，目前的努力集中在开发杀死或清除病毒库的新方法（例如SAHA），开发产生抗感染细胞的新方法（例如CCR 5的锌指核酸酶）和增强对HIV的免疫控制。肿瘤坏死因子相关凋亡诱导因子（TNF related apoptosis inducing factor，TRAIL）是一种主要功能是作为免疫监视效应子的分子，并且它与恶性肿瘤以及包括HIV在内的病毒感染的发病机制有关。关于TRAIL在HIV中的作用，相当多的证据支持在体内HIV感染期间发生的TRAIL失调的作用，并且有充分的证据表明，用外源性TRAIL处理来自接受HAART的HIV感染患者的细胞减少了潜伏感染细胞的数量，如通过定量共培养测定中不可检测水平的可复制病毒所测量的。由于TRAIL由效应细胞表达（即，CD 8和/或NK细胞），我们质疑为什么TRAIL依赖性天然免疫机制不能独立地减少潜伏感染细胞的数量。我们发现来自HIV感染患者的细胞产生一种新的TRAIL剪接变体，我们称之为TRAIL短，它拮抗正常的TRAIL信号传导。因此，我们提出了一个模型，通过HIV感染的细胞产生TRAIL短，防止这些细胞被CTL或NK细胞杀死，这使得一个子集的感染细胞持续存在。目前的研究计划涉及了解这种TRAIL剪接变体的生物学特性，并开发抑制这种变体的方法，我们将其命名为TRAILshort（TRAILs）。由于我们已经产生了初步数据，其表明TRAIL阻断HIV诱导的CD 4 T细胞的杀伤，以及CTL和NK细胞诱导的杀伤，我们现在提出抑制TRAIL作为增加HIV感染的CD 4 T细胞死亡速率的手段，从而有助于根除HIV感染的细胞的目标，并治愈HIV感染。在这方面，我们有额外的初步数据表明，抑制TRAIL实现了增加对HIV感染的T细胞的杀伤，并增强CTL和NK细胞对靶细胞的杀伤的目标。