The HIV envelope but not VSV glycoprotein is capable of mediating HIV latent infection of resting CD4 T cells.
The HIV envelope but not VSV glycoprotein is capable of mediating HIV latent infection of resting CD4 T cells.
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DOI：
10.1371/journal.ppat.1000633
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发表时间：
2009-10
期刊：
影响因子：
6.7
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Yu D;Wang W;Yoder A;Spear M;Wu Y
HIV融合和进入CD4 T细胞由两种受体CD4和CXCR 4介导。这种受体需求可以通过用介导病毒通过内吞进入的水泡性口炎病毒糖蛋白（VSV-G）假型化病毒体来消除。VSV-G假型HIV对转化细胞具有高度感染性，尽管病毒绕过了病毒受体和肌动蛋白皮质。在HIV感染中，与受体结合的gp120也传递信号。最近，我们证明了在HIV潜伏感染血液静息CD4 T细胞中对CXCR4信号传导的独特要求。因此，我们进行了平行研究，其中VSV-G假型HIV在没有辅助受体信号传导的情况下用于感染转化的和静息的T细胞。我们的研究结果表明，在转化的T细胞中，VSV-G假型导致较低的病毒DNA合成，但较高的核迁移率。然而，在静止的CD4 T细胞中，只有HIV病毒介导的进入，而不是VSV-G介导的内吞，可以导致病毒DNA合成和核迁移。通过内吞途径进入的病毒颗粒在1 - 2天内被破坏。这些结果表明，VSV-G介导的内吞途径，虽然在转化细胞中有活性，是有缺陷的，不是一个途径，可以建立HIV潜伏感染的初级静息T细胞。我们的研究结果强调了真正的HIV包膜及其在血液静息T细胞潜伏感染中的信号传导能力的重要性。这些结果也呼吁谨慎的内吞进入模型的HIV-1，并在数据解释VSV-G假型HIV用于识别HIV限制因子在静息T细胞。虽然受体介导的病毒内吞作用或与细胞膜的融合可以通过多种表面分子来实现，但反复选择两种趋化因子受体CCR5或CXCR4作为主要的HIV进入辅助受体意味着迫切需要利用免疫系统中的趋化过程。细胞骨架重排和细胞迁移是趋化性信号传导的主要结果。然而，先前发表的数据表明，剥夺病毒的信号传导能力赋予更高的感染性，通过VSV-G介导的内吞进入转化细胞。我们重新讨论了趋化因子辅助受体信号传导和皮质肌动蛋白在HIV-1潜伏感染静息CD4 T细胞中的作用，其中病毒可以建立潜伏期，并在T细胞活化后进行生产性复制。我们的研究结果证实，只有真正的HIV-1包膜蛋白，而不是VSV-G，是能够介导潜伏感染的休息CD4 T细胞。这些发现强调了HIV包膜及其在HIV感染其天然靶细胞中的信号传导能力的重要性。
HIV fusion and entry into CD4 T cells are mediated by two receptors, CD4 and CXCR4. This receptor requirement can be abrogated by pseudotyping the virion with the vesicular stomatitis virus glycoprotein (VSV-G) that mediates viral entry through endocytosis. The VSV-G-pseudotyped HIV is highly infectious for transformed cells, although the virus circumvents the viral receptors and the actin cortex. In HIV infection, gp120 binding to the receptors also transduces signals. Recently, we demonstrated a unique requirement for CXCR4 signaling in HIV latent infection of blood resting CD4 T cells. Thus, we performed parallel studies in which the VSV-G-pseudotyped HIV was used to infect both transformed and resting T cells in the absence of coreceptor signaling. Our results indicate that in transformed T cells, the VSV-G-pseudotyping results in lower viral DNA synthesis but a higher rate of nuclear migration. However, in resting CD4 T cells, only the HIV envelope-mediated entry, but not the VSV-G-mediated endocytosis, can lead to viral DNA synthesis and nuclear migration. The viral particles entering through the endocytotic pathway were destroyed within 1–2 days. These results indicate that the VSV-G-mediated endocytotic pathway, although active in transformed cells, is defective and is not a pathway that can establish HIV latent infection of primary resting T cells. Our results highlight the importance of the genuine HIV envelope and its signaling capacity in the latent infection of blood resting T cells. These results also call for caution on the endocytotic entry model of HIV-1, and on data interpretation where the VSV-G-pseudotyped HIV was used for identifying HIV restriction factors in resting T cells. While receptor-mediated viral endocytosis or fusion with the cell membrane can be achieved through multiple surface molecules, the repetitious selection of two chemokine receptors, CCR5 or CXCR4, as the main HIV entry coreceptor implies an urgent viral need to exploit the chemotactic process in the immune system. Cytoskeletal rearrangement and cell migration are the primary consequences of chemotactic signaling. Nevertheless, previously published data demonstrated that depriving the virus of its signaling ability conferred higher infectivity through VSV-G-mediated endocytotic entry in transformed cells. We revisited the issue of chemokine coreceptor signaling and the role of cortical actin in HIV-1 latent infection of resting CD4 T cells, in which the virus can establish latency with a potential for productive replication upon T cell activation. Our results confirmed that only the genuine HIV-1 envelope protein, but not VSV-G, is capable of mediating latent infection of resting CD4 T cells. These findings highlight the importance of the HIV envelope and its signaling capacity in HIV infection of its natural target cells.
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