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标题: 巴斯德所揭示HIV-1黏膜感染(性传播)新机制 [打印本页]

作者: Biodog    时间: 2016-1-8 17:36
标题: 巴斯德所揭示HIV-1黏膜感染(性传播)新机制
12月30日,国际学术期刊Journal of Virology在线发表了中科院上海巴斯德研究所王建华课题组最新研究成果(Human mucosal mast cells capture HIV-1 and mediate viral trans-infection of CD4+ T cells),揭示HIV-1黏膜感染(性传播)新机制。

性传播是当前HIV-1最主要的传播方式。生殖道黏膜、直肠或口腔黏膜组织为HIV-1的性传播提供了主要的感染位点,HIV-1黏膜感染过程尚不清楚。一般认为,亚黏膜组织中定位的宿主细胞(如树突状细胞、巨噬细胞等)能够介导病毒向淋巴结的转运,在HIV-1初始感染中起到主导作用,提示这些免疫细胞在HIV-1感染中具有双刃剑作用。探讨宿主细胞介导的HIV-1传播感染,分析其在病毒建立初始感染中的作用,对于剖析HIV-1黏膜感染过程和寻找相应的抑制策略具有重要的意义。课题组以前的工作曾对树突状细胞介导HIV-1感染CD4+ T细胞(Trans-infection)的分子机制进行了系统的研究。本研究揭示亚黏膜组织中定位的肥大细胞同样可以捕捉HIV-1介导病毒感染T细胞。

肥大细胞主要分布于机体与外界环境接触的部位,如皮肤、消化道、肠道和生殖道黏膜等,是首先接触到病原体或过敏原的宿主细胞之一。肥大细胞最常见的报道是与哮喘、过敏等相关。肥大细胞可调节天然免疫和获得性免疫反应,近年来,其在抵御细菌、真菌、寄生虫和病毒等病原体入侵中的重要作用被逐渐重视。亚黏膜定位的肥大细胞与树突状细胞、巨噬细胞一样,是HIV-1黏膜侵染首先接触的宿主细胞。近期报道显示,肥大细胞在HIV-1感染妇女子宫颈组织中分布明显增加,提示肥大细胞在HIV-1感染中的可能作用。

博士研究生江爱平和研究助理蒋金凤等在王建华研究员的指导下,与南京医科大学附属江苏省人民医院、上海市第六人民医院、复旦大学附属上海市公共卫生临床中心,及美国Tulane灵长类研究中心等单位合作,从结肠癌旁组织黏膜中分离肥大细胞,分析其与HIV-1的相互作用。研究发现肥大细胞表达HIV-1受体或辅佐受体,可被HIV-1直接感染;更重要的是,发现肥大细胞表达C-型凝集素分子DC-SIGN、整合素α4β7及硫酸肝素等分子,作为HAF( HIV attachment factor),能够结合HIV-1,然后把捕捉的感染性病毒颗粒传递给CD4+ T细胞,扩大HIV-1的传播感染。研究揭示了肥大细胞在HIV-1黏膜感染中的作用和分子机制,对于发展相应的HIV-1黏膜感染阻断策略具有重要的意义。

该研究得到中科院、国家基金委及科技部艾滋病和病毒性肝炎重大传染病防治专项的资助。

图:黏膜肥大细胞捕捉HIV-1介导感染CD4+ T细胞。(A)电镜下观察肥大细胞捕捉HIV-1病毒,箭头表示病毒颗粒; (B) 示意图:黏膜组织肥大细胞介导HIV-1传播感染。

摘要:
The gastrointestinal mucosa is the primary site at where HIV-1 invades, amplifies and becomes persistently established, and cell to cell transmission of HIV-1 infection plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and have been showed increased density in HIV-infected women genital mucosa. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic and bacterial infections. However the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs) DC-SIGN, HSPG, α4β7 integrin, and mediated capture of HIV-1 on the cell surface. Intriguingly, following co-cultured with CD4+ T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. The prior-blocking with anti-HAFs antibody or manan before co-culture impaired viral trans-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and were required for efficient cell to cell HIV-1 transmission. Our results revealed a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection.
IMPORTANCE In this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1 trans-infection of CD4+ T cells. The finding facilitates understanding of HIV-1 mucosal infection and benefits the strategy development to combating primary HIV-1 dissemination.






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