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.

项目摘要逆转录病毒是包裹的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，慢性感染。由于不断攻击细胞基因组通过逆转录病毒，哺乳动物细胞产生了限制因素，可以禁止其感染。这些因素之一是，塞林掺入剂5（serinc5）通过逆转录病毒阻止细胞感染掺入萌芽病毒的信封中，并防止信封融合和孔的步骤感染期间早期与靶细胞膜形成；因此，使病毒无法感染。 Serinc5限制了多种逆转录病毒，例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）。先前的工作表明Nef和Glycogag，艾滋病毒和MLV蛋白分别通过从质膜隔离并因此抑制SERINC5，从而抑制它阻止Serinc5保险在萌芽的病毒中 - 使它们充满感染。虽然很多有关Serinc5在体外的功能的信息，对其在体内的功能知之甚少。我们在这里提议检查逆转录病毒感染期间Serinc5的体内功能迄今完成了。我们计划通过使用两种方法来做到这一点：a）使用serinc5 ko小鼠，b）使用甘氨酸突变病毒或表达NEF的MLV病毒。在这项工作中，我们建议研究Serinc5的作用在限制体内逆转录病毒感染及其在牛奶传播逆转录病毒中的作用。此外，由使用表达NEF的MLV病毒，我们打算检查体内Nef-Serinc5的相互作用和重要性体内感染期间的这种相互作用。这项研究将为Serinc5的作用提供急需的见解在体内逆转录病毒感染期间，还有可能创建新模型以测试治疗治疗人类逆转录病毒感染的策略。