Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses
Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses
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DOI：
10.1128/jvi.00381-07
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Chen, Benjamin K.
中科院分区：
文献类型：
--
作者：
Chen, Ping;Huebner, Wolfgang;Chen, Benjamin K.
无细胞的人类免疫缺陷病毒1型（HIV-1）可以引发感染，但感染和未感染的T细胞之间的接触可以增强病毒通过称为病毒突触（VS）的细胞间结构的传播。VS对无细胞病毒转移的相对贡献尚未仔细测量。使用超灵敏的荧光病毒转移试验，我们估计当表达HIV的Jurkat T细胞和原代CD 4（+）T细胞之间形成VS时，细胞相关的病毒转移比无细胞病毒的吸收效率高18，000倍。此外，与无细胞病毒摄取相反，VS将病毒快速沉积到靶T细胞中的局灶性胰蛋白酶抗性区室中。这种大量的病毒内化需要Env-CD 4受体相互作用，但对抑制同源无细胞病毒的患者来源的中和抗血清的抑制具有抗性。删除Env胞质尾并不消除VS介导的转移，但它使VS对中和抗体敏感，表明尾限制了VS中和表位在感染细胞表面上的暴露。VS的动态实时成像显示，HIV表达细胞被极化，并通过尾足样结构与靶细胞进行持续的Env依赖性接触。极化的T细胞形态，Env-CD 4协调粘附，和病毒从HIV感染的细胞转移到未感染的细胞表明，VS允许HIV-1逃避抗体中和和有效传播。未来的研究将确定这种大规模的病毒转移在多大程度上有助于通过携带病毒的T细胞的迁移进行生产性感染或病毒传播。
Cell-free human immunodeficiency virus type 1 (HIV-1) can initiate infections, but contact between infected and uninfected T cells can enhance viral spread through intercellular structures called virological synapses (VS). The relative contribution of VS to cell-free viral transfer has not been carefully measured. Using an ultrasensitive, fluorescent virus transfer assay, we estimate that when VS between HIV-expressing Jurkat T cells and primary CD4(+) T cells are formed, cell-associated transfer of virus is 18,000-fold more efficient than uptake of cell-free virus. Furthermore, in contrast to cell-free virus uptake, the VS deposits virus rapidly into focal, trypsin-resistant compartments in target T cells. This massive virus internalization requires Env-CD4 receptor interactions but is resistant to inhibition by patient-derived neutralizing antisera that inhibit homologous cell-free virus. Deleting the Env cytoplasmic tail does not abrogate VS-mediated transfer, but it renders the VS sensitive to neutralizing antibodies, suggesting that the tail limits exposure of VS-neutralizing epitopes on the surface of infected cells. Dynamic live imaging of the VS reveals that HIV-expressing cells are polarized and make sustained, Env-dependent contacts with target cells through uropod-like structures. The polarized T-cell morphology, Env-CD4 coordinated adhesion, and viral transfer from HIV-infected to uninfected cells suggest that VS allows HIV-1 to evade antibody neutralization and to disseminate efficiently. Future studies will discern to what extent this massive viral transfer contributes to productive infection or viral dissemination through the migration of virus-carrying T cells.