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

描述(由申请人提供)：关于慢病毒，如人类免疫缺陷病毒1型(HIV-1)为什么进入潜伏期，以及潜伏期在感染的自然历史中是否起到任何作用，我们的知识存在一个根本性的缺口。这些信息对于识别潜在储集层的回弹机制是至关重要的。HIV-1病毒已导致3000万人死亡 全世界有3600万人感染了艾滋病毒-1/艾滋病，目前还没有有效的艾滋病毒-1疫苗。现有的用于治疗HIV-1的抗逆转录病毒疗法(ARTS)无法治愈感染患者，因为HIV-1通过潜伏感染CD4+T细胞进入休眠状态。由此产生的潜伏蓄水池寿命很长，确保了病毒的终生存留，并被认为是 治愈HIV-1病毒的最大障碍。流行的和被接受的观点是，潜伏期是ART所表现出的一种“意外”，在人类免疫缺陷病毒的自然历史过程中，它对病毒没有健康益处。 感染(即，这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健康益处，那么替代治疗策略可能比目前的策略更有效。长期目标是设计替代治疗策略来解决HIV-1潜伏期的问题。这项提议的直接目标是确定潜伏期是否对HIV-1的健康有利。基于最近的研究表明，在粘膜的初始感染是病毒的恶劣环境，我们的中心假设是潜伏期通过在粘膜的初始感染期间保护病毒免受恶劣条件的影响而赋予病毒选择性优势。这个项目的基本原理是，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量化模型，并在一个新的实验细胞培养系统中测试该模型。这项拟议的研究将在艾滋病毒长期潜伏问题上开辟新的天地。这将是首次尝试应用病毒进化的现代理论工具来测试HI-1潜伏期的适合性作用。这一贡献意义重大，因为如果潜伏期给HIV-1带来了健康优势， 目前的根除策略正在与进化的病毒表型作斗争，这可能是非常具有挑战性的。如果确定潜伏期是否是一种进化的特征，它将在很大程度上改变艾滋病毒-1治疗研究，从根除(例如“激活并杀死”方法)转向遏制策略(这可能代表一种“功能治疗”)。

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').