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

基本信息

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
项目类别：
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

项目摘要

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 感染需要识别所有隐藏潜伏感染的细胞储存库。我们从 18 名接受长期抗逆转录病毒治疗的无病毒血症患者中的 14 名中，从高度纯化的 Vd2 类 T 细胞中回收到了潜伏但具有复制能力的 HIV。当仅培养 15,000 个细胞时，HIV 就被回收，这反映了感染的高频率。我们发现，原代分离的外周血 Vd2 细胞可以通过激活诱导的上调而在体外被感染。 CD4 受体，并提出 HIV 诱导的免疫激活可能导致 d T 细胞在体内感染。我们建议扩大对 Vd2 T 细胞潜伏感染的研究，调查 Vd1 T 细胞以确定它们是否也被潜伏感染，并且然后进行纵向研究以验证这种新储存库的持久性并更准确地定量感染，然后我们将探索这些细胞中的潜伏期是否可以。我们的团队正在开发针对中央记忆 CD4+ T 细胞内潜伏期的相同治疗方法，或者如果需要针对该储存库的新的、特定于 d T 细胞的方法，那么最后，考虑到组织内 d T 细胞的优势，我们将破坏这种治疗方法。直接研究这些细胞在 GALT 和淋巴结组织中的感染和潜伏期，我们的研究将为定义和攻击持续、潜伏感染细胞内的 HIV 感染做出重要贡献。