The Role of Gamma Delta T Cells as Persistent Reservoirs of HIV Infection

Gamma Delta T 细胞作为 HIV 感染持久储存库的作用

• 批准号: 9034786
• 负责人: DAVID M. MARGOLIS
• 金额: $ 49.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-05 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034786
• 关键词: Acute; Antiviral Therapy; Biological Assay; CD4 Antigens; CD4 Positive T Lymphocytes; Cells; Cellular biology; Chronic; Evaluation; Farnesyl Transferase Inhibitor; Frequencies; Gut associated lymphoid tissue; HIV; HIV Infections; Health; Histone Deacetylase Inhibitor; Human; In Vitro; Infection; Investigation; Licensing; Longitudinal Studies; Lymph Node Tissue; Lymphocyte; Lymphoid Tissue; Maintenance; Memory; Mucous Membrane; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Population; Reagent; Residual state; Rest; Role; Source; Surveys; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Tissues; Up-Regulation; Viral; Virus; Virus Diseases; Vorinostat; antiretroviral therapy; bisphosphonate; bone loss; cell type; chemokine receptor; design; gastrointestinal; immune activation; in vivo; interest; intraepithelial; latent infection; latent persistent infection; memory CD4 T lymphocyte; novel; novel strategies; pathogen; peripheral blood; protein farnesyltransferase; purge; receptor expression

 DESCRIPTION (provided by applicant): Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. We have discovered that d T cells constitute an unexpected but substantial reservoir of persistent, latent infection. We recovered latent but replication-competent HIV from highly purified T cells of the Vd2 class from 14 of 18 aviremic patients on long-standing antiretroviral therapy. In nine of these 14 patients, HIV was recovered when as few as 15,000 cells were cultured, reflecting a high frequency of infection. We found that primary isolated peripheral blood Vd2 cells can be infected in vitro through activation-induced upregulation of the CD4 receptor and propose that HIV-induced immune activation may allow infection of d T cells in vivo. We propose to extend our studies of latent infection in Vd2 T cells, survey Vd1 T cells to determine if they are latently infected as well, and then perform longitudinal studies to verify the persistence and more accurately quantitate infection in this new reservoir. We will then explore whether latency in these cells can be disrupted by the same therapeutic approaches that our group is developing to target latency within central memory CD4+ T cells, or if novel, d-specific approaches to this reservoir are needed. Finally, given the predominance of d T cells within the tissue we will directly study infection and latency of these cells in GALT and lymph node tissue. Our investigations will contribute critically to the effort to define and attack HIV infection within persistent, latently infected cells.

 描述（由申请人提供）：根除HIV感染需要识别所有潜伏感染的细胞储库。我们已经发现d T 细胞构成了一个意想不到的，但实质性的持久性，潜伏性感染的水库。我们从18例长期接受抗逆转录病毒治疗的病毒血症患者中的14例的高度纯化的Vd2类T细胞中回收了潜伏但具有复制能力的HIV。在这14名患者中，有9名患者在培养了15，000个细胞时就恢复了HIV，这反映了感染的高频率。我们发现，主要分离的外周血Vd2细胞可以在体外感染，通过激活诱导的上调的CD4受体，并提出艾滋病毒诱导的免疫激活可能允许感染的D T细胞在体内。我们建议扩展我们对Vd2 T细胞中潜伏感染的研究，调查Vd1 T细胞以确定它们是否也被潜伏感染，然后进行纵向研究以验证这种新储库中的持久性并更准确地定量感染。然后，我们将探讨这些细胞的潜伏期是否可以 被我们小组正在开发的靶向中枢记忆CD4+ T细胞内潜伏期的相同治疗方法所破坏，或者如果需要针对该储存库的新的d特异性方法。最后，鉴于组织内d T细胞的优势，我们将直接研究这些细胞在GALT和淋巴结组织中的感染和潜伏期。我们的研究将有助于在持续的、潜伏感染的细胞中定义和攻击HIV感染。