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：
9887341
负责人：
Spyridon Stavrou
金额：
$ 23.63万
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/9887341
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.

项目概要逆转录病毒是有包膜的 RNA 病毒，可以感染包括人类在内的多种物种，并导致由于逆转录病毒DNA的不断攻击，导致慢性感染。通过逆转录病毒改变细胞基因组，哺乳动物细胞已经发展出限制因子，可以阻止它们这些因素之一，丝氨酸整合子 5 (SERINC5) 通过被逆转录病毒阻断细胞的感染。掺入出芽病毒粒子的包膜中并阻止包膜融合和孔的步骤在感染早期与靶细胞膜形成；从而使病毒体无法感染。 SERINC5 限制多种逆转录病毒，如人类免疫缺陷病毒 (HIV)、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 gluGag（一种 HIV）。和 MLV 蛋白分别通过将 SERINC5 与质膜隔离来抑制 SERINC5，从而抑制 SERINC5 阻止 SERINC5 掺入萌芽病毒体中，使它们完全具有传染性。关于 SERINC5 的体外功能信息已知，但对其体内功能知之甚少。建议检查逆转录病毒感染期间 SERINC5 的体内功能，这一点尚未被证实到目前为止，我们计划使用两种方法来做到这一点：a）利用 SERINC5 KO 小鼠；b）使用 gluGag 突变病毒或表达 Nef 的 MLV 病毒在这项工作中，我们建议检查 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。使用表达 Nef 的 MLV 病毒，我们打算检查 Nef-SERINC5 在体内的相互作用及其重要性这项研究将为了解 SERINC5 的作用提供急需的见解。在体内逆转录病毒感染过程中，也有可能创建用于测试疗法的新模型治疗人类逆转录病毒感染的策略。