Effects of HIV infection on resident memory T cells

HIV 感染对常驻记忆 T 细胞的影响

• 批准号: 9325422
• 负责人: Laura Pattacini
• 金额: $ 22万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325422
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Anti-Retroviral Agents; Antigens; Archives; Biopsy; Blood; CCR5 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cell Count; Cells; Cervical; Collaborations; Data; Development; Drug or chemical Tissue Distribution; Etiology; FOXP3 gene; Frequencies; HIV; HIV Infections; HIV Seropositivity; HIV therapy; Highly Active Antiretroviral Therapy; Human Herpesvirus 8; Human Papillomavirus; Immune; Immune response; Immunologics; Impairment; Individual; Infection; Interleukin-15; Kaposi Sarcoma; Life; Link; Location; Lung; Lymphoid; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Memory; Methodology; Modification; Molecular Profiling; Mucous Membrane; Names; Neoplastic Cell Transformation; Organ; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Production; Public Health; Quality of life; RANTES; Recruitment Activity; Regulatory T-Lymphocyte; Role; Sampling; Skin; Solid; Staining method; Stains; Suspensions; Swab; T memory cell; TNF gene; Tissue Stains; Tissues; Transforming Growth Factor beta; Universities; Viral; Virus; Virus Activation; Virus Diseases; Virus Replication; Washington; Woman; antiretroviral therapy; base; cell type; cytokine; cytotoxic; global health; improved; in vitro Assay; macrophage; migration; neoplastic; neoplastic cell; novel; novel strategies; overexpression; pathogen; pre-exposure prophylaxis; prevent; public health relevance; rectal; response; therapeutic vaccine; tumor

 DESCRIPTION (provided by applicant): HIV therapy now counts more than 30 anti-retroviral antiretroviral drugs that largely improved life conditions and prolonged AIDS-free survival. Nevertheless, no definitive cure is yet available for the life-long condition. One of the major problems related to obtaining a definitive cure, is the establishment of the so-called reservoirs o infection, where HIV can remains for decades in a latent state. New approaches are seeking to re-activate viral replication so that immune cells can while ART blocks infection of new cells. Moreover, some cancers are more frequent in HIV-infected patients, in some instances even when they are receiving antiretroviral therapy. Furthermore, antiretroviral therapy is available to less then half of the people living with HIV. Our proposal aims at exploring the effects of HIV on an immune cell type characterized by location in tissues and prompt response to a second encounter with the antigen. For their rapid response and location such cells, named resident memory T cells, might be perfect candidates eliminate latently infected cells upon re-activation of viral replication. We also propose to explore the role that these cells, or their lack, have in limiting neoplastic transformation in two different cancer model, cervical cancer and Kaposi sarcoma, both AIDS-defining cancers. Based on our preliminary results, we expect that HIV affect migration of CD8+ TRM cells. We think that this reduction in cell number, perhaps accompanied by modification of function, might facilitate the maintenance of the HIV reservoir as well as the neoplastic transformation linked to viral infection. To our knowledge, this will be the first project exploring the effects and modification of TRM in HIV infection as well as the possible consequences of such impairment. The project is built on a solid methodology: immunofluorescent staining of tissues in order to identify CD4 and CD8 TRM has been established in our Lab and will allow us to determine not only the number, but as well the location of such cells. Further immunofluorescent staining as well as in vitro assays will allow exploring a path we repute as being cause for the reduced number of TRM, a decrease in number of regulatory T cells, therefore of TGF-beta, a cytokine described to be important in overexpression of CD69. The results of the study will allow to clarify whether TRM numbers are altered by HIV and if their re- instauration can help reducing the latently infected cells as well s HIV-related cancers.

 描述（由申请人提供）：艾滋病毒治疗现在有30多种抗逆转录病毒药物，大大改善了生活条件，延长了无艾滋病生存期。然而，目前还没有确切的治愈方法来治疗这种终身疾病。与获得最终治愈相关的主要问题之一是建立所谓的感染库，其中艾滋病毒可以以潜伏状态保持数十年。新的方法正在寻求重新激活病毒复制，使免疫细胞可以在ART阻断新细胞感染的同时。此外，有些癌症在艾滋病毒感染者中更常见，在某些情况下，即使他们正在接受抗逆转录病毒治疗。此外，抗逆转录病毒疗法可用于 不到一半的艾滋病毒携带者。我们的建议旨在探索艾滋病毒对免疫细胞类型的影响，其特征在于组织中的位置和对第二次遇到抗原的迅速反应。由于它们的快速反应和定位，这种细胞被称为常驻记忆T细胞，可能是在病毒复制重新激活时消除潜伏感染细胞的完美候选者。我们还建议探索这些细胞或它们的缺乏在两种不同的癌症模型中限制肿瘤转化的作用，宫颈癌和卡波西肉瘤，这两种癌症都是艾滋病定义的癌症。基于我们的初步结果，我们预期HIV影响CD 8 + TRM细胞的迁移。我们认为，这种细胞数量的减少，可能伴随着功能的改变，可能有助于维持HIV储存库以及与病毒感染相关的肿瘤转化。据我们所知，这将是第一个探索TRM在HIV感染中的作用和修饰以及这种损害可能产生的后果的项目。该项目是建立在一个坚实的方法：组织的免疫荧光染色，以确定CD 4和CD 8的TRM已经建立在我们的实验室，将使我们能够确定不仅是数量，但以及这些细胞的位置。进一步的免疫荧光染色以及体外测定将允许探索我们认为是TRM数量减少、调节性T细胞数量减少、因此TGF-β（一种被描述为在CD 69过表达中重要的细胞因子）减少的原因的途径。这项研究的结果将有助于澄清TRM数量是否被HIV改变，以及它们的重新恢复是否有助于减少潜伏感染的细胞以及HIV相关的癌症。