Paving the Way for a Novel Therapeutic Approach to Combat HIV

为对抗艾滋病毒的新治疗方法铺平道路

• 批准号: 8358310
• 负责人: Martin Prlic
• 金额: $ 264万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358310
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Apoptotic; CD4 Positive T Lymphocytes; Cause of Death; Cell Survival; Cells; Cessation of life; Development; Family; Goals; HIV; HIV Infections; HIV vaccine; Human; Immune response; Immune system; Infection; Malignant Neoplasms; Metabolic; Metabolism; Morbidity - disease rate; Prevention; Prophylactic treatment; Regimen; Rest; Risk; Signal Transduction; System; T-Lymphocyte; Testing; Tumor Necrosis Factor-alpha; Viral; Virus; abstracting; base; combat; fighting; improved; member; microbicide; mortality; novel therapeutic intervention; optogenetics; pandemic disease; prevent; public health relevance

DESCRIPTION (Provided by the applicant) Abstract: Two strategies are currently in place to control the HIV pandemic: (1) anti-retroviral treatment reduces HIV-associated morbidity and mortality by controlling viral replication in infected subjects, thus also reducing the risk of viral dissemination; and (2) a comprehensive prevention package, including HIV vaccines, microbicides and pre-exposure prophylaxis regimens is being tested and aims at preventing new infections. Substantial effort has been invested in continuously improving these strategies, but there are several limitations to their further enhancement, many of which are related to HIV's vast mutational capacity. Instead of further refining current efforts that are confined by the limitations of these two strategies, we propose to introduce a third strategy. Our aim is to directly preserve the viability of uninfected CD4 T cells but not activated, infected cells, thus maintaining a functional immune system and limiting viral replication. HIV infection causes the loss of na¿ve CD4 T cells, which incapacitates the adaptive immune response and thus ultimately leads to AIDS, the inability to fight off infections and development of certain cancers. The vast majority of CD4 T cells die without actually being infected. We propose to rescue these na¿ve bystander CD4 T cells by targeting T cell metabolism. We present a strategy that aims to exploit the metabolic differences of uninfected, resting CD4 T cells and infected, activated CD4 T cells to selectively save the former but not the latter. This strategy is based on controlling the activity of pro-apoptotic BH3 family and tumor necrosis factor (TNF) superfamily members to control CD4 T cell viability. We propose to dissect how various metabolic signals are integrated in primary human CD4 T cells to regulate these apoptotic effector molecules using the recently established system of optogenetics. We propose that our strategy has merit to serve as a stand-alone approach or could be used in conjunction with both existing strategies to control the HIV pandemic. Public Health Relevance: HIV has caused the death of more than 25 million people. Despite efforts to limit mortality and further spreading of the virus there were still 2.6 million new infections and 1.8 million deaths in 2009. We propose a new strategy to combat this pandemic by manipulating T cell metabolism to prevent CD4 T cell loss and maintain a functional immune system with the goal of eliminating viral replication.

描述(由申请人提供) 摘要：目前有两个战略来控制艾滋病毒大流行：(1)抗逆转录病毒治疗通过控制感染对象中的病毒复制来减少艾滋病毒相关的发病率和死亡率，从而也降低了病毒传播的风险；(2)正在测试包括艾滋病毒疫苗、杀菌剂和暴露前预防方案在内的综合预防方案，旨在防止新的感染。在不断改进这些战略方面投入了大量的努力，但进一步加强这些战略有几个限制，其中许多与艾滋病毒的巨大变异能力有关。我们建议引入第三个战略，而不是进一步完善目前受到这两个战略限制的努力。我们的目标是直接保存未感染的CD4T细胞的活性，而不是激活的、受感染的细胞，从而维持正常的免疫系统并限制病毒复制。HIV感染导致NAVE CD4T细胞的丧失，使其丧失能力 适应性免疫反应，从而最终导致艾滋病，无法抵抗感染和某些癌症的发展。绝大多数CD4T细胞在没有实际感染的情况下死亡。我们建议通过靶向T细胞代谢来挽救这些天然的旁观者CD4T细胞。我们提出了一种策略，旨在利用未感染的静止的CD4T细胞和感染的激活的CD4T细胞的代谢差异来选择性地挽救前者，而不是后者。这一策略是基于控制促凋亡的BH3家族和肿瘤坏死因子超家族成员的活性来控制CD4T细胞的活性。我们建议利用最近建立的光遗传学系统，剖析不同的代谢信号如何整合到原代人类CD4T细胞中，以调节这些凋亡效应分子。我们认为，我们的战略具有作为一种独立办法的优点，或者可以与两种现有战略结合使用，以控制艾滋病毒大流行。 公共卫生相关性：艾滋病毒已导致2500多万人死亡。尽管努力限制死亡率和病毒的进一步传播，但2009年仍有260万新感染病例和180万死亡病例。我们提出了一种新的策略，通过控制T细胞代谢来防止CD4T细胞丢失，并维持功能正常的免疫系统，以消除病毒复制。