HIV-infected T cells are migratory vehicles for viral dissemination.
HIV-infected T cells are migratory vehicles for viral dissemination.
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DOI：
10.1038/nature11398
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发表时间：
2012-10-11
期刊：
影响因子：
64.8
通讯作者：
Mempel, Thorsten R.
中科院分区：
文献类型：
--
作者：
Murooka, Thomas T.;Deruaz, Maud;Marangoni, Francesco;Vrbanac, Vladimir D.;Seung, Edward;von Andrian, Ulrich H.;Tager, Andrew M.;Luster, Andrew D.;Mempel, Thorsten R.
通过粘膜表面进入宿主后，HIV-1 传播到淋巴组织以建立免疫系统的全身感染。该病毒在传播早期阶段在允许的靶细胞中局部传播以及在随后的传播过程中全身传播的机制尚不清楚。体外研究表明，感染和未感染 T 细胞之间稳定接触期间病毒学突触 (VS) 的形成大大提高了病毒转移的效率。然而，尚不清楚 T 细胞接触在体内是否足够稳定，以允许在上皮和淋巴组织中细胞永久运动的条件下形成功能性突触。在这里，我们使用多光子活体显微镜（MP-IVM）检查了人源化小鼠淋巴结（LN）中感染 HIV 的 T 细胞的动态行为。我们发现，大多数有效感染的 T 细胞能够强劲迁移，从而使其均匀分布在整个 LN 皮质中。一部分受感染细胞通过 HIV 包膜 (Env) 依赖性细胞融合形成多核合胞体。合胞体的不协调运动以及与 CD4+ LN 细胞的粘附导致长膜系链的形成，使细胞长度增加至迁移未感染 T 细胞的 10 倍。阻止迁移性 T 细胞从淋巴结进入传出淋巴液，从而中断 T 细胞再循环，限制 HIV 传播并大大降低血浆病毒血症。因此，我们发现感染 HIV 的 T 细胞具有活动性，形成合胞体，并建立束缚相互作用，从而促进通过 VS 的细胞间传播。虽然它们在淋巴结中的迁移会局部传播感染，但 T 细胞通过组织的再循环对于有效的全身病毒传播非常重要，这表明了对抗 HIV 感染的新分子靶标。
After host entry through mucosal surfaces, HIV-1 disseminates to lymphoid tissues to establish a generalized infection of the immune system. The mechanisms by which this virus spreads among permissive target cells locally during early stages of transmission, and systemically during subsequent dissemination are not known. In vitro studies suggest that formation of virological synapses (VSs) during stable contacts between infected and uninfected T cells greatly increases the efficiency of viral transfer. It is unclear, however, if T cell contacts are sufficiently stable in vivo to allow for functional synapse formation under the conditions of perpetual cell motility in epithelial and lymphoid tissues. Here, using multiphoton intravital microscopy (MP-IVM), we examined the dynamic behavior of HIV-infected T cells in lymph nodes (LNs) of humanized mice. We found that most productively infected T cells migrated robustly, resulting in their even distribution throughout the LN cortex. A subset of infected cells formed multinucleated syncytia through HIV envelope (Env)-dependent cell fusion. Both uncoordinated motility of syncytia as well as adhesion to CD4+ LN cells led to the formation of long membrane tethers, increasing cell lengths to up to 10 times that of migrating uninfected T cells. Blocking the egress of migratory T cells from LNs into efferent lymph, and thus interrupting T cell recirculation, limited HIV dissemination and strongly reduced plasma viremia. Thus, we have found that HIV-infected T cells are motile, form syncytia, and establish tethering interactions that may facilitate cell-to-cell transmission through VSs. While their migration in LNs spreads infection locally, T cell recirculation through tissues is important for efficient systemic viral spread, suggesting new molecular targets to antagonize HIV infection.
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影响因子：
6.7
作者：
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通讯作者：
Schwartz O
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