MARCH Proteins, Members of a Host Protein Family that Targets HIV

项目摘要/摘要 膜相关环CH(MARCH)蛋白是E3环泛素连接酶，与 膜受体的调节。这个泛素连接酶家族是在发现K3和K5之后出现的，这两个 卡波西肉瘤相关疱疹病毒(KSHV)中的病毒三月同源物，这些同源物在逃避 宿主通过泛素化并随后去除主要组织相容性复合体类而产生的免疫反应 第二类(MHC-II)受体从细胞表面释放，从而阻断抗原提呈。蜂窝手机 MARCH蛋白家族由11个成员组成，结构相似，包含一个环-CH结构域 这对于靶向膜受体(如MHC-II)的清除和内化是至关重要的。最近的报道 研究表明，3月蛋白也可以有效地限制人类免疫缺陷病毒1型(HIV-1)的感染。 3月1日、2日和8日通过阻止病毒包膜的结合来限制艾滋病毒和其他逆转录病毒 萌芽中的病毒粒子。这项提案探索了3月介导的抗逆转录病毒机制的一些方面，这些机制具有 以前从未被研究过。目前，还没有关于病毒蛋白中和的信息。 三月蛋白质。这项研究计划的第一个目的是研究艾滋病毒编码因子 在感染期间中和MARCH8。第二个目的是检查HIV-1信封对来自 不同亚型对3月介导的限制以及不同亚型HIV-1蛋白的能力 以对抗MARCH8。初步研究表明，随着时间的推移，HIV-1会对3月的限制产生抵抗力。 第三个目标将确定使HIV-1基因组对三月抑制产生抵抗力的变化。 最后，第四个目标将解决其他3月蛋白在HIV-1感染中的作用。总而言之，这些 研究将为三月蛋白的抗逆转录病毒作用提供新的线索，并将解决三月蛋白的某些方面-- 介导的HIV-1抑制作用，这是以前尚未确定的。最后，这些蛋白质具有很强的潜力。 作为抗逆转录病毒治疗药物开发的临床靶点。

Project Summary/ Abstract Membrane Associated RING CH (MARCH) proteins are RING E3 ubiquitin ligases that are implicated in the regulation of membrane receptors. This family of ubiquitin ligases emerged after the discovery of K3 and K5, two viral MARCH-homologues in Kaposi’s sarcoma associated herpesvirus (KSHV), which are critical in evading the host’s immune response by ubiquitinating and subsequently removing the major histocompatibility complex class II (MHC-II) receptors from the surface of the cells and therefore blocking antigen presentation. The cellular MARCH family of proteins consists of 11 members that share structural similarity and contain a RING-CH domain that is essential for the removal and internalization of target membrane receptors (e.g. MHC-II). Recent reports showed that MARCH proteins can also potently restrict human immunodeficiency virus 1 (HIV-1) infection. MARCH1, 2 and 8 restrict HIV-1 and other retroviruses by blocking the incorporation of the viral envelope in the budding virions. This proposal explores aspects of the MARCH-mediated antiretroviral mechanism that have never been previously studied. Currently, there is no information concerning a viral protein that counteracts MARCH proteins. The first aim of this research plan examines the mechanism by which an HIV encoded factor counteracts MARCH8 during infection. The second aim examines the susceptibility of HIV-1 envelopes from different subtypes to MARCH-mediated restriction as well as the ability of HIV-1 proteins from different subtypes to counteract MARCH8. Preliminary studies show that HIV-1 over time becomes resistant to MARCH restriction. The third aim will determine the changes in the HIV-1 genome that render it resistant to MARCH inhibition. Finally, the fourth aim will address the role of the other MARCH proteins on HIV-1 infection. In summary, these studies will shed new light on the anti-retroviral role of MARCH proteins and will address aspects of MARCH- mediated HIV-1 inhibition that have not been previously determined. Finally, these proteins have strong potential as clinical targets for the development of antiretroviral therapeutics.