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（申请人提供） 摘要：目前有两种控制HIV大流行的策略：（1）抗逆转录病毒治疗通过控制感染受试者的病毒复制来降低与HIV相关的发病率和死亡率，从而降低了病毒传播的风险； （2）正在测试一个全面的预防软件包，包括HIV疫苗，微生物和暴露前预防方案，并旨在防止新的感染。已经为继续改善这些策略的大量努力投入了大量努力，但是它们的进一步增强有几个局限性，其中许多与艾滋病毒的巨大突变能力有关。我们提出了第三种策略，而不是进一步完善当前的努力，而不是由这两种策略的局限性限制。我们的目的是直接保留未感染的CD4 T细胞的生存力，但未激活，感染细胞，从而维持功能性免疫系统并限制病毒复制。 HIV感染会导致NA¿VECD4 T细胞的丧失，这无能力 自适应免疫响应，因此最终导致艾滋病，无法抵抗感染和某些癌症的发展。绝大多数CD4 T细胞死亡而没有实际感染。我们建议通过靶向T细胞代谢来挽救这些NA旁观者CD4 T细胞。我们提出了一种旨在探索未感染的，静止的CD4 T细胞并感染活化的CD4 T细胞的代谢差异的策略，以选择性地保存前者，但不能保存后者。该策略基于控制凋亡的BH3家族和肿瘤坏死因子（TNF）超家族成员的活性以控制CD4 T细胞活力。我们建议剖析如何使用最近建立的光遗传学系统在原代人CD4 T细胞中整合各种代谢信号，以调节这些凋亡效应分子。我们建议我们的策略有价值作为一种独立的方法，或者可以与控制艾滋病毒大流行的两种现有策略一起使用。 公共卫生相关性：艾滋病毒已导致超过2500万人死亡。尽管限制了病毒死亡率和进一步传播，但在2009年仍有260万个新感染和180万人死亡。我们提出了一种新策略，通过操纵T细胞代谢来抵抗这种大流行，以防止CD4 T细胞丧失并保持功能性免疫系统，以消除病毒复制。