Lymphatic endothelial cells promote productive and latent HIV infection in resting CD4+ T cells.
Lymphatic endothelial cells promote productive and latent HIV infection in resting CD4+ T cells.
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DOI：
10.1186/s12985-018-1068-6
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发表时间：
2018-10-03
期刊：
影响因子：
4.8
通讯作者：
Shen A
中科院分区：
文献类型：
--
作者：
Schilthuis M;Verkaik S;Walhof M;Philipose A;Harlow O;Kamp D;Kim BR;Shen A
艾滋病毒治愈尚未实现，因为潜伏的病毒库持续存在，特别是在静息的CD 4 + T淋巴细胞中。在体外，很难用HIV-1感染静止的CD 4 + T细胞，但在体内很容易发生感染。内皮细胞（EC）排列在淋巴组织中的淋巴管中，并在体内定期与静息的CD 4 + T细胞相互作用。其他人和我们已经表明，EC促进静息CD 4 + T细胞的生产性和潜伏性HIV感染。然而，在以前的研究中使用的EC是来自人脐带（HUVEC），这是大血管;而EC驻留在淋巴组织是微血管。在这项研究中，我们研究了微血管EC刺激静息CD 4 + T细胞在建立病毒感染和潜伏期的影响。将人静息和活化的CD 4 + T细胞单独培养或与内皮细胞一起培养，并用假型病毒感染。用流式细胞术测量由绿色荧光蛋白表达指示的感染水平，并使用Flowing软件和Excel分析数据。我们证实，EC从淋巴组织（LEC）能够促进HIV感染和潜伏期的形成，在静息的CD 4 + T细胞，同时保持他们在静息表型，IL-6参与LEC刺激的CD 4 + T细胞。然而，LEC和HUVEC的刺激之间存在一些差异。与HUVEC刺激不同，我们证明了静息记忆T细胞的LEC刺激不依赖于主要组织相容性复合物II类（MHC II）与T细胞受体（TCR）的相互作用，并且CD 2-CD 58相互作用不参与静息T细胞的LEC刺激。LEC分泌的IL-6水平也低于HUVEC。我们还发现LEC刺激增加了活化的CD 4 + T细胞中的HIV感染率。虽然观察到淋巴EC和HUVEC之间T细胞刺激的差异，但我们证实，与大血管EC刺激类似，微血管EC刺激促进直接HIV感染和静息CD 4 + T细胞中的潜伏期形成，而无需T细胞活化。LEC刺激也增加了活化的CD 4 + T细胞的感染率。此外，本研究建立了EC与静息CD 4 + T细胞相互作用的生理学更相关的模型，并进一步强调了研究EC在HIV感染和静息和活化CD 4 + T细胞潜伏期中的作用的重要性。
An HIV cure has not yet been achieved because latent viral reservoirs persist, particularly in resting CD4+ T lymphocytes. In vitro, it is difficult to infect resting CD4+ T cells with HIV-1, but infections readily occur in vivo. Endothelial cells (EC) line the lymphatic vessels in the lymphoid tissues and regularly interact with resting CD4+ T cells in vivo. Others and we have shown that EC promoted productive and latent HIV infection of resting CD4+ T cells. However, the EC used in previous studies were from human umbilical cords (HUVEC), which are macrovascular; whereas EC residing in the lymphoid tissues are microvascular. In this study, we investigated the effects of microvascular EC stimulation of resting CD4+ T cells in establishing viral infection and latency. Human resting and activated CD4+ T cells were cultured alone or with endothelial cells and infected with a pseudotyped virus. Infection levels, indicated by green fluorescent protein expression, were measured with flow cytometry and data was analyzed using Flowing Software and Excel. We confirmed that EC from lymphatic tissue (LEC) were able to promote HIV infection and latency formation in resting CD4+ T cells while keeping them in resting phenotype, and that IL-6 was involved in LEC stimulation of CD4+ T cells. However, there are some differences between stimulation by LEC and HUVEC. Unlike HUVEC stimulation, we demonstrated that LEC stimulation of resting memory T cells does not depend on major histocompatibility complex class II (MHC II) interactions with T cell receptors (TCR) and that CD2-CD58 interactions were not involved in LEC stimulation of resting T cells. LEC also secreted lower levels of IL-6 than HUVEC. We also found that LEC stimulation increases HIV infection rates in activated CD4+ T cells. While differences in T cell stimulation between lymphatic EC and HUVEC were observed, we confirmed that similar to macrovascular EC stimulation, microvascular EC stimulation promotes direct HIV infection and latency formation in resting CD4+ T cells without T cell activation. LEC stimulation also increased infection rates in activated CD4+ T cells. Additionally, the present study established a physiologically more relevant model of EC interactions with resting CD4+ T cells and further highlighted the importance of investigating the roles of EC in HIV infection and latency in both resting and activated CD4+ T cells.
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