Glycosphingolipid Composition of Human Immunodeficiency Virus Type 1 (HIV-1) Particles Is a Crucial Determinant for Dendritic Cell-Mediated HIV-1 trans-Infection
Glycosphingolipid Composition of Human Immunodeficiency Virus Type 1 (HIV-1) Particles Is a Crucial Determinant for Dendritic Cell-Mediated HIV-1 trans-Infection
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DOI：
10.1128/jvi.02249-08
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发表时间：
2009-04-15
影响因子：
5.4
通讯作者：
Gummuluru, Suryaram
中科院分区：
文献类型：
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作者：
Hatch, Steven C.;Archer, Jacob;Gummuluru, Suryaram
人类免疫缺陷病毒1型（HIV-1）与树突状细胞（DC）的相互作用是多因子的，可能需要HIV-1包膜糖蛋白gp120与DC表面表达的分子之间的非冗余相互作用，这些分子决定了病毒颗粒的细胞命运。令人惊讶的是，中和与dc的HIV-1 gp120依赖性结合相互作用不足以阻止HIV-1附着。除了gp120外，HIV-1颗粒还在其颗粒膜中结合宿主细胞来源的蛋白质和脂质。在这项研究中，我们证明了宿主细胞来源的鞘糖脂（GSLs）在HIV-1颗粒与未成熟和成熟dc的初始相互作用中起着至关重要的作用。由神经酰胺合成酶抑制剂伏马菌素B1或葡萄糖神经酰胺合成酶抑制剂1-苯基-2-decanoylamino-3-morpholino-1-丙醇（PDMP）处理的病毒产生细胞产生HIV-1颗粒，导致病毒颗粒的产生，尽管能够结合先前定义的HIV-1 gp120特异性附着因子CD4， DC-SIGN和syndecans，但它们被未成熟和成熟DCs捕获的能力减弱。此外，gsl缺陷HIV-1颗粒在dc - t细胞共培养中建立生产性感染的能力受到抑制。这些研究为HIV-1颗粒膜相关的GSL在病毒侵袭dc中的作用提供了初步证据，也为开发抗病毒治疗提供了新的细胞靶点、GSL生物合成途径和GSL依赖性HIV-1与dc的相互作用。
Interactions of human immunodeficiency virus type 1 (HIV-1) with dendritic cells (DCs) are multifactorial and presumably require nonredundant interactions between the HIV-1 envelope glycoprotein gp120 and molecules expressed on the DC surface that define the cellular fate of the virus particle. Surprisingly, neutralization of HIV-1 gp120-dependent binding interactions with DCs was insufficient to prevent HIV-1 attachment. Besides gp120, HIV-1 particles also incorporate host cell-derived proteins and lipids in their particle membrane. In this study, we demonstrate a crucial role for host cell-derived glycosphingolipids (GSLs) for the initial interactions of HIV-1 particles with both immature and mature DCs. Production of HIV-1 particles from virus producer cells treated with ceramide synthase inhibitor fumonisin B1 or glucosylceramide synthase inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol ( PDMP) resulted in the production of virus particles that, although capable of binding previously defined HIV-1 gp120-specific attachment factors CD4, DC-SIGN, and syndecans, were attenuated in their ability to be captured by both immature and mature DCs. Furthermore, GSL-deficient HIV-1 particles were inhibited in their ability to establish productive infections in DC-T-cell cocultures. These studies provide initial evidence for the role of HIV-1 particle membrane-associated GSLs in virus invasion of DCs and also provide additional novel cellular targets, GSL biosynthetic pathways and GSL-dependent HIV-1 interactions with DCs, for development of antiviral therapy.