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）：我们的知识上存在一个基本差距，即为什么慢病毒（例如人类免疫缺陷病毒1型（HIV-1））输入潜伏期以及潜伏期是否在自然感染史上起任何作用。这些信息是至关重要的，以确定潜在储层的弹性机制。 HIV-1杀死了3000万全球人，有3600万人患有HIV-1/AIDS，HIV-1没有有效的疫苗。用于治疗HIV-1的可用抗逆转录病毒疗法（ARTS）无法治愈受感染的患者，因为HIV-1通过潜在感染CD4+ T细胞进入休眠状态。由此产生的潜在水库长期存在，确保病毒的终生持久性，并被认为是 HIV-1治疗的最大障碍。盛行和公认的观点是，潜伏期是艺术表现出的“事故”，对这种病毒在自然史上没有任何适应性益处感染（即，它不是病毒的发展特征）。但是，没有证据表明这种观点是延迟是事故，如果延迟为病毒提供适应性益处，替代治疗策略可能比当前的策略更有效。长期目标是设计替代治疗策略来解决HIV-1潜伏期的问题。该提案的直接目的是确定延迟是否为HIV-1提供适合性益处。基于o最近的研究表明，粘膜膜的初始感染是该病毒的严峻环境，我们的中心假设是，潜伏期通过在粘膜膜的初始感染期间保护该病毒的选择性优势。该项目的理由是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，我们将开发一个多尺度定量模型，将潜伏期与病毒传播联系起来，并在新型的实验细胞培养系统中测试该模型。拟议的研究将在长期的艾滋病毒潜伏期问题中打破新的基础。这将是使用病毒进化的现代理论工具来测试HI-1潜伏期的健身角色的第一个努力。这项贡献是重要的，因为如果延迟赋予HIV-1的健身优势，当前的根除策略正在与进化的病毒表型作斗争，这可能是极具挑战性的。确定潜伏期是否是进化的性状，它将大大改变HIV-1从根除（例如“激活和杀伤方法”的方法）到遏制策略（可能代表“功能治疗”）。