Therapeutic targets in gammaherpesvirus infection

伽马疱疹病毒感染的治疗靶点

• 批准号: 10296371
• 负责人: ERIC T CLAMBEY
• 金额: $ 54.53万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-21 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296371
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Affect; Antibodies; Antiviral Agents; Attenuated; Attenuated Vaccines; B-Lymphocytes; Biological; Biological Models; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Differentiation process; Cells; Cues; DNA Tumor Viruses; Data; Dendritic Cells; Detection; Development; Disease; Frequencies; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immune Evasion; Immune system; Immunity; Immunocompetent; Immunosuppression; In Vitro; Inactivated Vaccines; Individual; Infection; Inflammatory; Integration Host Factors; Interferon Type II; Kaposi Sarcoma; Knowledge; Lytic Phase; Macrophage Activation; Malignant Neoplasms; Medical; Methods; Mus; Myelogenous; Myeloid Cells; Non-Hodgkin' s Lymphoma; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Population; Primary Infection; Process; Protocols documentation; Regulation; Research Proposals; Risk; Role; Stimulus; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Tropism; Vaccination; Vaccines; Viral; Virus; Virus Diseases; acute infection; adaptive immune response; base; cell type; cytokine; defined contribution; gammaherpesvirus; high dimensionality; human pathogen; in vivo; infected B cell; insight; interest; latency-associated nuclear antigen; latent infection; macrophage; mouse model; pathogen; prevent; response; single cell analysis; success; targeted treatment; therapeutic target; vaccine efficacy; vaccine trial

PROJECT SUMMARY The human gammaherpesviruses (γHVs) Kaposi's sarcoma associated herpesvirus and Epstein-Barr virus are DNA tumor viruses that establish a lifelong infection. These viruses are strongly associated with pathogenic outcomes in immune suppression, including the AIDS defining malignancies Kaposi's sarcoma and non- Hodgkin lymphoma. A major challenge of the γHVs is that these viruses present a lifelong risk for viral re- emergence and pathogenesis, especially in the context of acquired or medically-induced immunosuppression. Lifelong infection is further confounded by the limited therapeutic interventions against γHV diseases. To date, the best defense against γHV-induced disease is an intact immune system. Despite this correlation, there remain major knowledge gaps in our understanding of: 1) protective aspects of successful vaccination to γHV infection, and 2) consequence of vaccination on the composition and frequency of infected cells, either before or after established infection. In this R01 application, we seek to investigate how vaccination alters γHV infection, using murine gammaherpesvirus 68 (γHV68), a mouse model of γHV infection, that facilitates study of infection and associated responses from primary infection through lifelong latency and re-emergence of lytic infection. We recently undertook studies to characterize how latency is regulated by viral and host factors at the single-cell level, identifying that the latent pool is heterogeneous based on expression of the latency- associated nuclear antigen (LANA), and that the proportion of LANA+ latently-infected cells is subject to regulation. These studies further identified that CD8 T cells, and the cytokine interferon-gamma, limit LANA+ latently-infected B cells, and that vaccination with a live-attenuated vaccine is capable of profoundly restricting LANA+ latent B cell infection in an interferon-gamma-independent manner. We now seek to investigate the role of myeloid cells in infection and vaccination on γHV infection both in vitro and in vivo. We will make use of vaccination protocols with defined differences in efficacy to identify the critical features using single cell analysis and high dimensional methods to distinguish the features of vaccine efficacy. We hypothesize that vaccination with a live-attenuated vaccine induces: 1) local and systemic myeloid reprogramming, which 2) redirects γHV myeloid infection into an immune-susceptible myeloid target. We will test this in three aims. First, we will analyze the impact of vaccination on local and systemic myeloid cells. Second, define how vaccination affects primary γHV infection of myeloid cells. Third, dissect how viral tropism is influenced by vaccine-induced effector mechanisms. By analyzing specific viral and host processes in the context of vaccines with varying efficacy, this proposal seeks to investigate myeloid reprogramming as a necessary, and therapeutically viable, target for vaccination against γHV latency.

项目摘要 人类γ掌病毒（γHVS）Kaposi的肉瘤相关疱疹病毒和爱泼斯坦 - 巴尔病毒是 建立终身感染的DNA肿瘤病毒。这些病毒与致病性密切相关 免疫抑制的结果，包括定义恶性肿瘤Kaposi的肉瘤和非艾滋病的艾滋病 霍奇金淋巴瘤。 γHV的主要挑战是，这些病毒会出现病毒式再生的终生风险 出现和发病机理，特别是在获得或医学诱导的免疫抑制的背景下。 对γHV疾病的治疗干预措施有限，终身感染进一步混淆。迄今为止， 对γHV诱导疾病的最佳防御是完整的免疫系统。尽管有这种相关性， 在我们对：1）成功疫苗接种到γHV的方面仍然是主要知识差距 感染和2）在感染细胞的组成和频率上进行疫苗接种的结果，以前 或建立感染后。在此R01应用中，我们试图研究疫苗接种如何改变γHV 感染，使用鼠γγ病毒68（γHV68），一种γHV感染的小鼠模型，促进了研究的研究。 感染和相关反应从原发性感染到终生潜伏期和裂解的重新出现 感染。我们最近进行了研究，以表征潜伏期如何受到病毒和宿主因素的调节 单细胞水平，确定潜在池是基于潜伏期的表达的异质性 相关的核抗原（LANA），LANA+潜在感染细胞的比例受 规定。这些研究进一步确定了CD8 T细胞和细胞因子干扰素γ限制了LANA+ 潜在感染的B细胞，该疫苗用活疫苗的疫苗能够深刻限制 LANA+潜在B细胞感染以干扰素γ的方式。我们现在寻求调查 髓样细胞在感染和疫苗接种中的作用在体外和体内γHV感染中的作用。我们将利用 疫苗接种方案具有定义的效率差异，可以使用单个单元格确定关键特征 分析和高维方法，以区分疫苗效率的特征。我们假设这一点 带有活疫苗的疫苗诱导的疫苗：1）局部和全身性髓样重编程， 2）将γHV髓样感染重定向到可免疫损伤的髓样靶靶标。我们将在此测试 三个目标。首先，我们将分析疫苗接种对局部和全身性髓样细胞的影响。第二，定义 疫苗接种如何影响髓样细胞的原发性γHV感染。第三，剖析病毒性向向性的影响如何 疫苗诱导的效应器机制。通过分析特定的病毒和宿主过程 该提案旨在调查髓样重新编程，并且 在治疗上可行的，针对γHV潜伏期的疫苗接种靶标。