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

项目摘要 识别和描述持续性HIV感染的所有细胞储存库至关重要 艾滋病毒根除工作。有越来越多的证据表明， 外周血，以及在身体的总淋巴细胞的大部分被淋巴细胞吸收的组织内。 所在我们已经发现，表达Vδ2 TCR链的γδ T细胞亚类具有潜伏性， 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CD4受体。我们已经证实了这一发现， 在感染后不到三周的急性HIV感染患者中， 在Vδ2细胞上表达CD4受体。 我们建议通过以下方式验证和阐明γδ T细胞内这种新的潜伏HIV储库的重要性： 将我们的研究扩展到包括互补Vδ1 TCR γδ T细胞群体，因为我们发现 ii）研究肠道中γ δ T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，因为γδ T细胞占优势 iii）分析γδ T细胞库内潜伏期的稳定性和持久性，以及iv） 探索破坏γδ T细胞内潜伏期的治疗方法。我们的调查将有助于 努力确定和根除所有持续性、潜伏性感染细胞中的艾滋病毒感染。

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.