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Human immunodeficiency virus type 1 envelope glycoprotein-dependent and -independent mechanisms of dendritic cell-mediated virus capture and trans infection.

机译:人类免疫缺陷病毒1型包膜树突状细胞介导的病毒捕获和反式感染的包膜糖依赖性和非依赖性机制。

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摘要

Dendritic cells promote human immunodeficiency virus type 1 (HIV-1) pathogenesis through trans infection, whereby HIV-1 particles are captured and transferred to CD4+ T cells without a productive dendritic cell (DC) infection. Though much of the research studying HIV-1/DC interactions has concentrated on HIV-1 envelope glycoprotein (gp120)-dependent attachment factors, specifically DC-specific intercellular adhesion molecule-3 (ICAM-3) grabbing non-integrin (DC-SIGN), there are multiple examples of HIV-1/DC attachment and transmission to T cells independent of DC-SIGN and other known attachment factors. Hence, our studies explored the relative contribution of gp120-dependent and -independent mechanisms of virus capture and trans infection by DCs. Initially, our studies focused on determining the mechanism of DC-SIGN-mediated HIV-1 internalization that might allow for virus to escape from degradative pathways in DCs. Specifically, we investigated the role of the transmembrane domain (TMD) of DC-SIGN in mediating lipid raft localization of DC-SIGN and endocytosis of HIV-1 particles. Despite introduction of mutations within putative lipid raft localization motifs or replacement of the DC-SIGN TMD with the TMD of a non-raft protein, transferrin receptor, we were unsuccessful in targeting DC-SIGN away from lipid rafts or inhibiting DC-SIGN-mediated HIV-1 endocytosis.;Interestingly, DCs can also capture HIV-1 particles derived from varied cellular sources, including primary CD4+ T cells and macrophages, independently of the glycoprotein, gp120. Besides gp120, HIV-1 particles also incorporate host cell-derived proteins and glycosphingolipids in their particle membrane. While protease treatment of virus particles did not affect virus capture by DCs, reduction in the glycosphingolipid (GSL) content of HIV-1 particles produced from cells treated with the GSL synthesis inhibitors, Fumonisin B1 (FB1) and 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), resulted in significant attenuation in virus capture by DCs, and inhibition of DC-mediated HIV-1 trans infection. Additionally, altering the location of HIV-1 assembly away from the plasma membrane to intracellular membranes via selective mutations in the viral matrix protein reduced the GSL content of virus-like particles and thereby inhibited DC-mediated capture of these particles. Together, these studies provide initial evidence for the role of HIV-1 particle membrane-associated GSLs in HIV-1 capture by DCs and as an important host-encoded determinant necessary for HIV-1 access to DC-mediated HIV-1 trans infection pathway.
机译:树突状细胞通过反式感染促进人类1型免疫缺陷病毒(HIV-1)的发病机理,从而将HIV-1颗粒捕获并转移到CD4 + T细胞,而无生产性树突状细胞(DC)感染。尽管许多研究HIV-1 / DC相互作用的研究都集中在HIV-1包膜糖蛋白(gp120)依赖性附着因子上,特别是DC特异性细胞间粘附分子3(ICAM-3)捕获非整联蛋白(DC-SIGN) ),有多个HIV-1 / DC附着和向T细胞传播的示例,这些信号独立于DC-SIGN和其他已知的附着因子。因此,我们的研究探索了gp120依赖性和非依赖性机制对DC捕获和反式感染病毒的相对作用。最初,我们的研究重点是确定DC-SIGN介导的HIV-1内在化的机制,该机制可能使病毒从DC的降解途径中逸出。具体来说,我们调查了DC-SIGN的跨膜结构域(TMD)在介导DC-SIGN的脂筏定位和HIV-1颗粒内吞作用中的作用。尽管在假定的脂筏定位基序中引入了突变,或用非筏蛋白,转铁蛋白受体的TMD替代了DC-SIGN TMD,但我们仍未能成功将DC-SIGN定位于脂筏之外或抑制DC-SIGN介导HIV-1内吞作用;有趣的是,DC也可以捕获来自多种细胞来源的HIV-1颗粒,包括原始CD4 + T细胞和巨噬细胞,而与糖蛋白gp120无关。除gp120以外,HIV-1颗粒还在其颗粒膜中掺入了宿主细胞衍生的蛋白质和鞘糖脂。尽管蛋白酶处理病毒颗粒不会影响DC捕获病毒,但减少了用GSL合成抑制剂,伏马菌素B1(FB1)和1-苯基-2-癸酰氨基处理的细胞产生的HIV-1颗粒的糖鞘脂(GSL)含量-3-吗啉代-1-丙醇(PDMP)导致DC捕获病毒的能力大大降低,并抑制DC介导的HIV-1反式感染。另外,通过病毒基质蛋白的选择性突变改变HIV-1装配体从质膜到细胞内膜的位置,可以减少病毒样颗粒的GSL含量,从而抑制DC介导的这些颗粒的捕获。总之,这些研究提供了与HIV-1颗粒膜相关的GSL在DCs捕获HIV-1中的作用的初步证据,并且是HIV-1进入DC介导的HIV-1反式感染途径所必需的重要的宿主编码决定因素。

著录项

  • 作者

    Hatch, Steven Carter.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Biology Molecular.;Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 266 p.
  • 总页数 266
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:36:52

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