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Experiment & Theory to Test an Evolutionary Fitness Role for Lentiviral Latency

实验

基本信息

批准号：
8891364
负责人：
Leor S Weinberger
金额：
$ 24.15万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891364
关键词：
Accidents Acquired Immunodeficiency Syndrome Address Alternative Therapies Bioreactors Blood CD4 Positive T Lymphocytes Cell Count Cell Culture System Cells Complement Containment Data Ensure Environment Evolution Focal Infection Foundations Goals HIV HIV-1 Health Individual Infection Knowledge Lead Life Link Lymphoid Lymphoid Tissue Mainstreaming Measures Membrane Modeling Monitor Mucous Membrane Natural History Outcome Patients Persons Pharmaceutical Preparations Phenotype Play Population Probability Regimen Reporter Research Research Personnel Rice Role Site Subfamily lentivirinae System Systemic infection Testing Therapeutic Vaccines Viral Viral Load result Virus antiretroviral therapy base design fighting fitness in vivo killings mathematical model nonhuman primate novel novel therapeutic intervention research study resilience theories tool trait transmission process

项目摘要

DESCRIPTION (provided by applicant): There is a fundamental gap in our knowledge as to why lentiviruses, such as the human immunodeficiency virus type 1 (HIV-1), enter latency and whether latency plays any role in the natural history of infection. This information is critically needed to identify the mechanism of resilience of the latent reservoir. HIV-1 has killed 30 million people worldwide, 36 million people are living with HIV-1/AIDS, and there is no effective vaccine for HIV-1. The available antiretroviral therapies (ARTs) for treating HIV-1 cannot cure infected patients because HIV-1 enters a dormant state by latently infecting CD4+ T cells. The resulting latent reservoirs are long lived, ensuring lifelong persistence of the virus, and are recognized as the greatest obstacle to an HIV-1 cure. The prevailing and accepted view is that latency is an "accident" manifested by ART and carries no fitness benefit for the virus in the natural history of infection (i.e., it is not an evolved trait of the virus). However, there is no evidence to supportthis view that latency is an accident and alternative therapy strategies might be more effective than current strategies if latency provides a fitness benefit for the virus. The long-term goal is to design alternative therapy strategies to address the problem of HIV-1 latency. The immediate objective of this proposal is to determine if latency provides a fitness benefit for HIV-1. Based o recent studies showing that initial infection at the mucosal membrane is a harsh environment for the virus, our central hypothesis is that latency confers a selective advantage for the virus by protecting it against harsh conditions during initial infection at mucosal membranes. The rationale for this project is that the knowledge acquired will help to identify new therapeutic approaches. To achieve our objective, we will develop a multi- scale quantitative model linking latency to virus transmission and test this model in a novel experimental cell- culture system. The proposed research will break new ground in the long-term HIV latency problem. It will be the first effort to apply modern theoretical tools of viral evolution to test a fitness role for HI-1 latency. This contribution is significant, because if latency confers a fitness advantage to HIV-1, current eradication strategies are fighting an evolved viral phenotype, which is likely to be exceptionally challenging. Determining if latency is an evolved trait it would substantially alter HIV-1 cure research from eradication (e.g. 'activate-and-kill' approaches) to containment strategies (which could represent a 'functional cure').

描述（由申请人提供）：对于慢病毒（例如人类免疫缺陷病毒 1 型 (HIV-1)）为何进入潜伏期以及潜伏期是否在感染的自然史中发挥作用，我们的知识存在根本性差距。这些信息对于确定潜在储层的恢复机制至关重要。 HIV-1 已导致 3000 万人死亡全世界有 3600 万人感染 HIV-1/艾滋病，并且没有有效的 HIV-1 疫苗。用于治疗 HIV-1 的现有抗逆转录病毒疗法 (ART) 无法治愈感染患者，因为 HIV-1 通过潜伏感染 CD4+ T 细胞而进入休眠状态。由此产生的潜伏储存库寿命较长，确保病毒终生持续存在，并被认为是 HIV-1 治愈的最大障碍。普遍接受的观点是，潜伏期是 ART 表现出来的“意外”，在自然史中对病毒没有任何适应性益处。感染（即，它不是病毒的进化特征）。然而，没有证据支持这种观点，即潜伏期是一种意外，如果潜伏期为病毒提供了适应性益处，那么替代治疗策略可能比当前策略更有效。长期目标是设计替代治疗策略来解决 HIV-1 潜伏期问题。该提案的直接目标是确定潜伏期是否对 HIV-1 具有适应性益处。最近的研究表明，粘膜的初始感染对于病毒来说是一个恶劣的环境，我们的中心假设是，潜伏期通过保护病毒在粘膜的初始感染期间免受恶劣条件的影响，从而赋予病毒选择性优势。该项目的基本原理是所获得的知识将有助于确定新的治疗方法。为了实现我们的目标，我们将开发一个将潜伏期与病毒传播联系起来的多尺度定量模型，并在新型实验细胞培养系统中测试该模型。拟议的研究将为解决艾滋病毒长期潜伏问题开辟新天地。这将是首次应用病毒进化的现代理论工具来测试 HI-1 潜伏期的适应性作用。这一贡献意义重大，因为如果潜伏期赋予 HIV-1 适应性优势，目前的根除策略正在对抗进化的病毒表型，这可能非常具有挑战性。确定潜伏期是否是一种进化特征，将大大改变 HIV-1 治疗研究，从根除（例如“激活并杀死”方法）到遏制策略（可能代表“功能性治疗”）。