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

• 批准号: 7642714
• 负责人: Chioma M Okeoma
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7642714
• 关键词: Acute; Animals; Anti-Retroviral Agents; Antigen-Presenting Cells; Antiviral Agents; B-Lymphocytes; Biological Models; Cells; Cultured Cells; Defect; Dendritic Cells; Genes; HIV-1; Hepatitis B Virus; Human; IL6 gene; Immune system; Immunity; Immunologic Receptors; Infection; Inflammatory; Inflammatory Response; Mediating; Mouse Mammary Tumor Virus; Murine leukemia virus; Mus; Pathway interactions; Pattern recognition receptor; Play; Primates; Production; Property; Proteins; Resistance; Retroviridae; Role; Spumavirus; Staging; Superantigens; System; T-Lymphocyte; Testing; Time; Tumor Virus Infections; Viral; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Work; cytokine; env Gene Products; in vivo; insight; mammary tumor virus; member; microorganism; mouse genome; mouse model; mouse toll-like receptor 4; pathogen; toll-like receptor 4; virus envelope

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）：APOBEC3（A3）蛋白是宿主细胞蛋白，赋予对病毒感染的内在免疫力。人类有七种 A3 蛋白，包括人类 A3 (hA3G) 和 hA3F。 hA3G 限制 Vif 缺陷型人类免疫缺陷病毒 1 (HIV-1)、灵长类泡沫病毒 (PFV)、乙型肝炎病毒 (HBV)、鼠白血病病毒 (MuLV) 和小鼠乳腺肿瘤病毒 (MMTV) 对培养细胞的感染。与人类相比，小鼠基因组编码单个 A3 基因 (mA3)，该基因限制 HIV-1、MuLV 和 MMTV 的感染。最近，我们提供了第一个体内证据，证明 A3 是一种抗病毒限制因子。通过比较 mA3 缺陷小鼠和 mA3 充足小鼠的 MMTV 感染，我们发现 mA3 在体内限制了该病毒的感染。最近，我们发现 mA3 限制树突状细胞 (DC) 中的 MMTV 感染，而树突状细胞是许多逆转录病毒感染的最初目标。这里提出的研究将利用 MMTV-mA3 模型系统来探索 mA3 与 MMTV 诱导的促炎细胞因子诱导之间的关系。最近，已经表明许多细胞因子诱导培养细胞中hA3G和hA3F的表达。众所周知，MMTV 在感染途径的两个步骤中诱导细胞因子产生：首先，当病毒包膜蛋白与先天免疫受体 Toll 样受体 4 (TLR4) 相互作用时，其次，当病毒感染的抗原呈递细胞（如 DC）向 T 细胞呈递病毒超抗原 (Sag) 时。因此，MMTV 感染也可能触发 mA3 的细胞表达。使用来自 mA3-/- 和 mA3+/+ 小鼠的 DC 的离体培养物，我们将研究细胞因子治疗是否诱导 mA3 表达以及这种诱导对 MMTV 感染的影响。我们还将开展动物研究并检查体内细胞因子诱导、mA3表达和病毒限制。为了确定 mA3 在感染途径的哪一步被诱导，我们将使用缺乏 mA3、MyD88、TRIP 和 TLR4 基因的小鼠以及无法对病毒 Sag 蛋白做出反应的小鼠。由于其抗病毒特性，在感染早期阶段较高的 mA3 表达可能有助于让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-mA3 模型系统来探索 mA3 的调节机制及其与更广泛的免疫系统的相互作用。事实上，有人建议通过使用诱导细胞因子产生的药物来增加 hA3G 表达可以用作抗 HIV-1 疗法。因此，我们的研究将增进对 A3 和免疫系统之间相互作用的理解，并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。