Nature Immune：研究发现细胞抗击病毒入侵的一种新防御机制

生物谷报道：UCLA科学家们在9月10日出版的Nature Immunology上报告说，他们鉴别出细胞抗击病毒入侵的一种新防御机制。病毒感染细胞、“劫持”宿主的酶和其它的构件来复制自己。为了达到实现的目的，病毒首先需要通过与宿主细胞的膜融合而进入细胞。但是，免疫系统也有一套对付这种侵犯的战略。           我们的免疫系统中有一种名为防御素（defensin retrocyclin 2, RC2)的蛋白质，它会对附近出现的病毒做出反应，从而阻止病毒与未感染细胞的融合。现在，科学家们在深入认识防御素如何防止病毒的融合方面迈出重要的一步。新发现将导致预防和治疗HIV和流感病毒感染的新方法。           为了认识防御素的抗病毒特性，Leonid  Chernomordik和同事研究了一种名为RC2的防御素，他们发现这种防御能抵御包括流感病毒在内的许多病毒。进一步的实验显示，RC2似乎是与细胞膜上的“糖”蛋白质结合在一起。这个过程阻止了细胞膜与病毒的融合，从而形成了细胞膜的一级防范禁止区，防止病毒的侵入。           研究人员将这种发现拓展到另外一种与糖结合的免疫分子，他们希望这种抗病毒战略有更广泛的应用。

Before a virus can invade a cell, glycoproteins on the viral and cell membranes must spread apart to allow the viral membrane to approach and merge with the cell membrane. Image Courtesy: NICHD. Defensins bind to glycoproteins, preventing them from spreading apart to allow membrane fusion. Image Courtesy: NICHD.

相关报道：

·台湾研究人员发现全新蛋白质防御素
·RNA沉默：古老的免疫防御机制对HIV-1束手无策

原文来源：

Leikina E, Delanoe-Ayari H, Melikov K, Cho MS, Chen A, Waring AJ, Wang W, Xie Y, Loo JA, Lehrer RI, Chernomordik LV. Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat Immunol. 2005 Sep 11; [PDF文件下载]

有关RC1，2的介绍：

BACKGROUND:  Defensins are cysteine-rich, cationic antimicrobial peptides expressed by leukocytes and epithelial cells of mammals and birds. These peptides, which can be considered endogenous antibiotics, play an important role in innate host defense against pathogens due to their antibacterial, antifungal and antiviral activities. Three defensin subfamilies exist in vertebrates: alpha-defensins, beta-defensins, and theta (circular) minidefensins. All of these have largely beta-sheet structures that are stabilized by three intramolecular cystine disulfide bonds, and derive from a common ancestral gene. Theta defensins are much smaller (18 amino acid residues) than alpha or beta defensins (29-45 residues), and their antiviral properties are considerably more robust than their antibacterial and antifungal effects.

INNOVATION: Retrocyclins 1 and 2 (also called RC-100 and RC100b) are novel circular peptides discovered by UCLA Researchers. Although they are produced synthetically, their structures are based on nucleotide sequences found in the human genome and/or in mRNA expressed by human bone marrow. Since human theta-defensin genes and retrocyclin bone marrow mRNA contain a premature stop codon in their signal sequence, retrocyclin peptides are probably not produced in humans. However, these peptides are found in certain Old World monkeys, and intact theta defensin genes are also present in lesser apes and orangutans (unpublished). Although the ability of theta defensins to kill bacteria is relatively modest, retrocyclin 1 and especially retrocyclin-2 show impressive activity against three different viral pathogens: human immunodeficiency virus (HIV-1), herpes simplex virus-1 and herpes simplex virus-2 (HSV-2). Although such broad specificity is somewhat reminiscent of interferons, retrocyclins operate as entry inhibitors. Retrocyclin-2 showed activity against a wide library of primary HIV-1 isolates of diverse subtypes, including subtypes A, B, C, CRF01, D, G, and recombinant subtypes. Its effectiveness was not dependent on or restricted by co-receptor (R5, X4 or R5X4) usage. The UCLA researchers are using retrocyclins-1 and 2 as platforms to develop analogs with improved pharmacotherapeutic properties.

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