Peripheral and tissue-resident gamm/delta T cells in HIV latency

项目摘要 识别和描述所有持续感染艾滋病毒的细胞宿主是至关重要的 致力于根除艾滋病毒的努力。越来越多的证据表明，该地区存在更多的潜在储层。 外周血，也在组织内，其中身体总淋巴细胞的很大一部分是 找到了。我们已经发现，表达V-γδ-2TCR链的δT细胞的一个亚类，潜伏着但 具有复制能力的艾滋病毒。此外，我们还描述了一种解释Vδ2细胞感染的机制， 这表明，尽管这些细胞通常表达极低水平的CD4受体，但它们可以 在体外刺激后上调CD_4受体。我们已经通过发现证实了这一发现 对感染后不到三周的急性艾滋病毒感染患者进行的研究发现，他们有大量的 V-δ-2细胞表面CD_4受体的表达 我们建议通过i)验证和澄清γδT细胞中这种新的潜伏艾滋病毒宿主的重要性。 扩展我们的研究以包括互补的Vδ1TCRγδT细胞群体，因为我们发现显著的水平 这第二个γδT细胞群体中的艾滋病毒DNA，II)研究肠道中γδT细胞内的感染和潜伏期 相关淋巴组织(GALT)、淋巴组织(LT)和肝脏，由于γδT细胞占优势 在这些组织中，iii)分析γδT细胞储存库中潜伏期的稳定性和持久性，以及iv) 探索扰乱γδT细胞内潜伏期的治疗方法。我们的调查将对 在所有持续的、潜伏感染的细胞中确定和根除艾滋病毒感染的努力。

Project Summary Identification and description of all cellular reservoirs of persistent HIV infection is of crucial importance to HIV eradication efforts. There is increasing evidence of the existence of additional latent reservoirs in the peripheral blood, and also within the tissue where a substantial fraction of the total lymphocytes of the body are located. We have discovered that a subclass of γδ T cells that express the Vδ2 TCR chain, harbor latent but replication-competent HIV. Furthermore, we have described a mechanism to explain Vδ2 cell infection, showing that although these cells generally express extremely low levels of the CD4 receptor, they can upregulate the CD4 receptor following stimuli in vitro. We have confirmed this finding by the discovery that acutely HIV-infected patients studied less than three weeks after infection, are found to have substantial expression of the CD4 receptor on Vδ2 cells. We propose to validate and clarify the importance of this new latent HIV reservoir within γδ T cells by i) extending our studies to include the complementary Vδ1 TCR γδ T cell population, as we find significant levels of HIV DNA within this second γδ T cell population, ii) studying infection and latency within γδ T cells in the gut associated lymphoid tissue (GALT), lymphoid tissues (LT) and liver, given the predominance of γδ T cells within these tissues, iii) analyze the stability and durability of latency within the γδ T cell reservoir, and iv) explore therapeutic approaches to disrupt latency within γδ T cells. Our investigations will contribute critically to the effort to define and eradicate HIV infection within all persistent, latently infected cells.