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The role of SERINC5 during retrovirus infection in vivo

SERINC5在体内逆转录病毒感染过程中的作用

基本信息

批准号：
10082429
负责人：
Spyridon Stavrou
金额：
$ 19.94万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-07 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082429
关键词：
Acquired Immunodeficiency Syndrome Affect Anti-Retroviral Agents Antiviral Agents CD4 Positive T Lymphocytes Cell membrane Cell surface Cells Clathrin Complex DNA Development Drug Targeting Endocytosis Equine Infectious Anemia Virus Gammaretrovirus Genome HIV HIV Genome HIV-1 Human In Vitro Infection Knockout Mice Light Mammalian Cell Mediating Membrane Proteins Milk Modeling Murine leukemia virus Mus Pathogenesis Phosphatidylserines Physiological Play Polyproteins Proteins RNA Viruses Research Retroviridae Retroviridae Infections Role Serine Sphingolipids Study Subject Study models Sum Viral Proteins Virion Virus Work chronic infection enhancer-binding protein AP-2 in vitro Assay in vivo insight member model development mutant nef Protein prevent protein function therapeutic evaluation therapeutic target trafficking transmission process virus envelope

项目摘要

Project summary Retroviruses are enveloped RNA viruses that can infect a variety of species, including humans, and result in chronic infection by integrating the retroviral DNA into the host’s genome. Because of the constant attack of the cellular genome by retroviruses, mammalian cells have developed restriction factors that can prohibit their infection. One of these factors, Serin incorporator 5 (SERINC5) blocks infection of cells by retroviruses by being incorporated in the envelope of the budding virions and preventing the step of the envelope fusion and pore formation with the target cell’s membrane early during infection; thus, rendering the virions incapable of infection. SERINC5 is restrictive to a variety of retroviruses such as human immunodeficiency virus (HIV), murine leukemia virus (MLV) and equine infectious anemia virus (EIAV). Previous work showed that Nef and glycoGag, an HIV and an MLV protein respectively, inhibit SERINC5 by sequestering it from the plasma membrane and thus blocking SERINC5 incorporation inside the budding virions -rendering them fully infectious. While a lot of information is known about the function of SERINC5 in vitro, little is known about its function in vivo. Here we propose to examine the in vivo function of SERINC5 during retrovirus infection, something that has not been hitherto done. We plan to do that by using two approaches: a) by utilizing SERINC5 KO mice and b) using a glycoGag mutant virus or a Nef-expressing- MLV virus. In this work we propose to examine the role of SERINC5 in restricting retrovirus infection in vivo and its role in milk borne transmission of retroviruses. Furthermore, by using a Nef-expressing MLV virus, we intend to examine the interplay of Nef-SERINC5 in vivo and the importance of this interaction during in vivo infection. This study will provide much needed insight into the role of SERINC5 during retrovirus infection in vivo, and also has the potential to create new models for testing therapeutic strategies for treating retroviral infections in humans.

项目总结逆转录病毒是有包膜的RNA病毒，可以感染包括人类在内的各种物种，并导致通过将逆转录病毒DNA整合到宿主的基因组中而导致的慢性感染。因为持续不断的攻击通过逆转录病毒的细胞基因组，哺乳动物细胞已经开发出限制因子，可以阻止他们的感染。其中一个因子，丝氨酸结合蛋白5(SERINC5)通过结合在萌发中的病毒粒子的包膜中，防止包膜融合和毛孔的步骤在感染早期与目标细胞膜形成；因此，使病毒粒子不能感染。 SERINC5对多种逆转录病毒具有限制性，如人类免疫缺陷病毒(HIV)、小鼠白血病病毒(MLV)和马传染性贫血病毒(EIAV)。先前的研究表明，Nef和gigGag是一种艾滋病毒和MLV蛋白分别通过将SERINC5与质膜隔离而抑制SERINC5，从而阻止SERINC5在萌芽中的病毒粒子内掺入-使它们完全具有传染性。虽然很多人目前对SERINC5的体外功能知之甚少，对其在体内的功能知之甚少。在这里我们建议检查SERINC5在逆转录病毒感染期间的体内功能，这是尚未得到证实的到目前为止，已经完成了。我们计划通过两种方法来做到这一点：a)利用SERINC5 KO小鼠和b)使用 Gagg突变病毒或表达Nef的MLV病毒。在这项工作中，我们建议研究SERINC5的作用限制体内逆转录病毒感染及其在逆转录病毒乳源性传播中的作用。此外，通过利用表达Nef的MLV病毒，我们打算研究Nef-SERINC5在体内的相互作用及其重要性在体内感染期间的这种相互作用。这项研究将对SERINC5的作用提供亟需的见解在体内逆转录病毒感染期间，也有可能创造新的模型来测试治疗治疗人类逆转录病毒感染的策略。