Cell reports：细胞间的HIV-1的转移才是CD4 T细胞死亡的罪魁祸首

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            近日，来自格莱斯顿研究所（Gladstone Institutes）的研究人员在国际杂志Cell Reports上发表了一篇研究论文，文中报道HIV并不是通过病毒直接感染宿主免疫细胞来引发AIDS，而是通过细胞间的病毒转移感染引起免疫细胞致死来引发AIDS。淋巴组织中CD4 T细胞的最基础的杀灭单元是其它感染的细胞而并不是游离的病毒。

  HIV-1可以通过两种方式来感染CD4 T 细胞。一种是游离的病毒直接感染，另一种是已经感染的细胞将病毒传输给未感染的细胞。而后者的感染效率大约是前者的1000至1000倍，本文研究表明后者感染方式可以诱发细胞内免疫链式反应，进而导致新感染细胞死亡，从而引发AIDS。

  研究人员利用HIV-1感染的淋巴组织，对比了游离病毒感染和细胞间转移两种方式引发的CD4 T细胞死亡率，结果发现，相比游离病毒感染而言，HIV在细胞间的感染往往会导致更加明显的CD4 T细胞的死亡。研究者还通过一系列方法扰乱了病毒的转移，包括对病毒进行遗传修饰、应用化学性的HIV抑制剂、阻断细胞间的突触传递等，证实了细胞间的接触是引起CD4 T细胞死亡的关键。重要的是，病毒直接感染细胞只会引发少数细胞发生凋亡（apoptosis）而死亡。但是通过已经感染的细胞将HIV-1传递给新的细胞会激活后者发生一种称为pyroptosis的死亡方式。这一死亡方式是DNA感受器识别反转录的DNA激活炎性小体，caspase-1活化而介导的。




  该研究揭示了HIV-1引发大量CD4 T细胞死亡的具体机制。让人们认识到通过阻断病毒在细胞间的传输，阻断CD4 T细胞的死亡或许才是治疗HIV-1引起的AIDS的有效手段。


本文由中国病毒学论坛原创，欢迎转载，转载请注明出处。

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Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells

Nicole L.K. Galloway, Gilad Doitsh, Kathryn M. Monroe, Zhiyuan Yang, Isa Muñoz-Arias, David N. Levy, Warner C. Greene

Highlights
•The mode of HIV-1 spread determines the outcome form of cell death
•Cell-to-cell spread is required to deplete non-permissive CD4 T cells via pyroptosis
•Free HIV-1 particles, even in large quantities, are unable to trigger pyroptosis
•The fundamental “killing units” of CD4 T cells are infected cells, not the virus

Summary
The progressive depletion of CD4 T cells underlies clinical progression to AIDS in untreated HIV-infected subjects. Most dying CD4 T cells correspond to resting nonpermissive cells residing in lymphoid tissues. Death is due to an innate immune response against the incomplete cytosolic viral DNA intermediates accumulating in these cells. The viral DNA is detected by the IFI16 sensor, leading to inflammasome assembly, caspase-1 activation, and the induction of pyroptosis, a highly inflammatory form of programmed cell death. We now show that cell-to-cell transmission of HIV is obligatorily required for activation of this death pathway. Cell-free HIV-1 virions, even when added in large quantities, fail to activate pyroptosis. These findings underscore the infected CD4 T cells as the major killing units promoting progression to AIDS and highlight a previously unappreciated role for the virological synapse in HIV pathogenesis.

http://www.cell.com/cell-reports/abstract/S2211-1247(15)00882-7