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

HIV潜伏期的外周和组织驻留γ/δ T细胞

• 批准号: 9204152
• 负责人: Natalia Soriano-Sarabia
• 金额: $ 47.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204152
• 关键词: Acute; Antiviral Therapy; Biological; CD4 Antigens; CD4 Lymphocyte Count; Cell physiology; Cells; Chronic Phase; Complement; DNA; Development; Early treatment; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Histone Deacetylase Inhibitor; Human; Immune response; Immune system; In Vitro; Infection; Investigation; Knowledge; Licensing; Life; Liver; Lymphocyte; Lymphoid Tissue; Measurement; Memory; Normal Range; Patients; Peripheral; Pharmaceutical Preparations; Population; Rest; Role; Signal Transduction; Site; Stimulus; Surface; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Time; Tissues; Viral; Viral reservoir; Virus; adaptive immunity; antiretroviral therapy; bone loss; gastrointestinal; in vivo; intraepithelial; latent infection; memory CD4 T lymphocyte; novel; peripheral blood

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.

项目概要 识别和描述持续性艾滋病毒感染的所有细胞储存库至关重要 消灭艾滋病毒的努力。越来越多的证据表明，该地区还存在着额外的潜在储库。 外周血，以及体内大部分淋巴细胞所在的组织内 位于。我们发现表达 Vδ2 TCR 链的 γδ T 细胞亚类具有潜在但 有复制能力的HIV。此外，我们描述了一种解释 Vδ2 细胞感染的机制， 表明虽然这些细胞通常表达极低水平的 CD4 受体，但它们可以 体外刺激后上调 CD4 受体。我们通过以下发现证实了这一发现： 研究人员在感染后不到三周的时间内对急性艾滋病毒感染者进行了研究，结果发现， Vδ2 细胞上 CD4 受体的表达。 我们建议通过 i) 验证和澄清 γδ T 细胞内这种新的潜在 HIV 储存库的重要性 将我们的研究扩展到包括互补的 Vδ1 TCR γδ T 细胞群，因为我们发现显着水平 第二个 γδ T 细胞群中 HIV DNA 的分析，ii) 研究肠道 γδ T 细胞内的感染和潜伏期 鉴于 γδ T 细胞占主导地位，相关淋巴组织 (GALT)、淋巴组织 (LT) 和肝脏 在这些组织内，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。我们的调查将至关重要 努力定义和根除所有持久性、潜伏感染细胞内的艾滋病毒感染。