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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）：为什么慢病毒，如人类免疫缺陷病毒1型（HIV-1）会进入潜伏期，以及潜伏期是否在感染的自然史中起任何作用，在我们的知识中存在根本性的空白。这一信息对于确定潜在水库的恢复机制至关重要。HIV-1已导致3000万人死亡