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Role of cytokine induction in APOBEC3-mediated virus restriction

细胞因子诱导在 APOBEC3 介导的病毒限制中的作用

基本信息

批准号：
8128423
负责人：
Chioma M Okeoma
金额：
$ 10.8万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2012-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): APOBEC3 (A3) proteins are host cellular proteins that confer intrinsic immunity to viral infections. Human have seven A3 proteins, including human A3 (hA3G) and hA3F. hA3G restricts infection of cells in culture by Vif-deficient human immunodeficiency virus 1 (HIV-1), primate foamy virus (PFV), hepatitis B virus (HBV), murine leukemia virus (MuLV), and mouse mammary tumor virus (MMTV). In contrast to humans, the mouse genome encodes a single A3 gene (mA3) which restrict infection by HIV-1, MuLV, and MMTV. Recently, we provided the first in vivo evidence that A3 is an antiviral restriction factor. By comparing MMTV infection in mice deficient in mA3 and their mA3-sufficient counterparts, we showed that mA3 restricted infection by this virus in vivo. More recently, we showed that mA3 restricts MMTV infection in dendritic cells (DCs), the initial targets of infection by many retroviruses. The studies proposed here will take advantage of the MMTV-mA3 model system to explore the relationship between mA3 and MMTV-induced pro-inflammatory cytokine induction. Recently, it has been shown that a number of cytokines induce expression of hA3G and hA3F in cultured cells. It is well-established that MMTV induces cytokine production at two steps in the infection pathway: first, when the virus envelope protein interacts with the innate immune receptor Toll-like receptor 4 (TLR4) and second, when virus-infected antigen presenting cells such as DCs present the viral superantigen (Sag) to T cells. Thus, it is likely that MMTV infection also triggers cellular expression of mA3. Using ex vivo cultures of DCs from mA3-/- and mA3+/+ mice, we will investigate if cytokine treatment induces mA3 expression and the effect of such induction on MMTV infection. We will also carry out animal studies and examine cytokine induction, mA3 expression and virus restriction in vivo. To determine at which step in the infection pathway mA3 is induced, we will use mice lacking mA3, MyD88, TRIP and TLR4 genes and mice unable to respond to the viral Sag protein. Because of its antiviral properties, higher mA3 expression during the early stages of infection may serve to allow the host's immune system time to limit virus infection. RELEVANCE: The proposed studies will use MMTV-mA3 model system to explore the regulatory mechanism(s) of mA3 and its interaction with the broader immune system. Indeed, it has been suggested that increasing hA3G expression through the use of agents that induce cytokine production could be used as an anti-HIV-1 therapy. Thus our studies will increase understanding of the cross-talk between A3 and the immune system and will set the stage for the use of this protein as a means of developing new anti-retroviral therapies

描述（由申请人提供）：APOBEC 3（A3）蛋白是赋予对病毒感染的固有免疫力的宿主细胞蛋白。人类有7种A3蛋白，包括人A3（hA 3G）和hA 3F。hA 3G限制Vif缺陷型人免疫缺陷病毒1（HIV-1）、灵长类泡沫病毒（PFV）、B肝炎病毒（HBV）、鼠白血病病毒（MuLV）和小鼠乳腺肿瘤病毒（MMTV）对培养物中细胞的感染。与人类相比，小鼠基因组编码单个A3基因（mA 3），其限制HIV-1、MuLV和MMTV的感染。最近，我们提供了第一个体内证据表明A3是一种抗病毒限制因子。通过比较MMTV感染小鼠缺乏mA 3和他们的mA 3-足够的同行，我们表明，mA 3限制这种病毒在体内的感染。最近，我们发现mA 3限制MMTV在树突状细胞（DC）中的感染，树突状细胞是许多逆转录病毒感染的初始靶点。本研究将利用MMTV-mA 3模型系统探讨mA 3与MMTV诱导的促炎细胞因子诱导的关系。最近，已经显示许多细胞因子诱导培养细胞中hA 3G和hA 3F的表达。已经确定MMTV在感染途径中的两个步骤诱导细胞因子产生：首先，当病毒包膜蛋白与先天免疫受体Toll样受体4（TLR 4）相互作用时，其次，当病毒感染的抗原呈递细胞如DC将病毒超抗原（Sag）呈递给T细胞时。因此，很可能MMTV感染也触发mA 3的细胞表达。使用来自mA 3-/-和mA 3 +/+小鼠的DC的离体培养物，我们将研究细胞因子处理是否诱导mA 3表达以及这种诱导对MMTV感染的影响。我们还将进行动物研究，并在体内检查细胞因子诱导，mA 3表达和病毒限制。为了确定在感染途径中的哪一步诱导mA 3，我们将使用缺乏mA 3、MyD 88、TRIP和TLR 4基因的小鼠和不能对病毒Sag蛋白应答的小鼠。由于其抗病毒特性，在感染的早期阶段较高的mA 3表达可能有助于使宿主的免疫系统有时间限制病毒感染。相关性：拟议的研究将使用MMTV-mA 3模型系统来探索mA 3的调节机制及其与更广泛的免疫系统的相互作用。事实上，已经提出通过使用诱导细胞因子产生的试剂来增加hA 3G表达可以用作抗HIV-1疗法。因此，我们的研究将增加对A3和免疫系统之间的相互作用的理解，并将为使用这种蛋白质作为开发新的抗逆转录病毒疗法的手段奠定基础