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Immunological control of a persistent viral infection

持续性病毒感染的免疫控制

基本信息

批准号：
7176814
负责人：
SALLY R. SARAWAR
金额：
$ 38.83万
依托单位：
TORREY PINES INST FOR MOLECULAR STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7176814
关键词：
Acquired Immunodeficiency Syndrome Adoptive Transfer Animal Model Antibodies Antibody Formation Antigen-Presenting Cells Antiviral Agents B-Lymphocytes Biological Assay Bone Marrow CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Chimera organism Class Cytolysis Dendritic Cells Dendritic cell activation Development Environment Epithelium Frequencies Herpesviridae Human Human Herpesvirus 4 Human Herpesvirus 8 Immune Immune response Immune system Immunocompromised Host Immunotherapeutic agent In Vitro Individual Infection Intranasal Administration Latent Virus Lead Licensing Ligation Longevity Longitudinal Studies Lung Lytic MHC Class II Genes Mediating Mus Numbers Opportunistic Infections Patients Peptides Play Protocols documentation Research Design Residual state Rodent Role Simplexvirus T-Lymphocyte TNF gene TNFRSF5 gene Testing Therapeutic Therapeutic Agents Time Tissues Transgenic Mice Treatment Protocols Up-Regulation Vaccines Viral Viral Antibodies Viral Antigens Virus Virus Diseases Work cell type cytokine design in vitro Assay in vivo latent infection mouse model novel novel therapeutics pathogen perforin prevent research study response

项目摘要

DESCRIPTION (provided by applicant): Reactivation of latent herpesviruses is a particular problem in immunocompromised individuals, such as AIDS patients, who lack effective CD4 T helper cell function. The ability to mobilize residual immune defenses to combat opportunistic infections in the absence of CD4 T cells would represent a tremendous therapeutic advantage to these patients. Infection of mice with murine gammaherpesvirus-68 (MHV-68) provides a useful small animal model for studying the long-term control of persistent viral infection and for testing the ability of potential therapeutic agents to control viral reactivation. MHV-68 is a naturally-occurring rodent pathogen and is closely-related to the human pathogens Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. MHV-68 replicates in the lungs of mice following intranasal administration and establishes a latent infection in B cells and epithelia. CD4 T cell-deficient mice can clear an initial challenge with virus, but fail to control latent virus, which reactivates in the lungs. Using this mouse model of opportunistic infection, we showed that treatment with an agonistic antibody to CD40 could substitute for CD4 T cell function and was highly effective in preventing reactivation of latent MHV-68 in lungs of CD4 T cell-deficient mice. Furthermore, our preliminary studies revealed that CD8 T cells are essential for this effect. However, it is not clear whether anti-CD40 treatment increases CD8 T cell function or works in conjunction with CD8 T cells, without changing their activity. The proposed studies are designed to dissect the mechanism by which anti-CD40 antibody treatment prevents viral reactivation in CD4 T cell-deficient mice, as follows: In Aim 1 we will determine the role of CD8 T cells. In Aim 2 we will determine the role of CD40-positive cells (such as B cells and dendritic cells). In Aim 3 we will determine the duration of the response, the number and frequency of treatments required and whether anti-CD40 treatment is effective against ongoing viral reactivation. The information obtained in these studies may be of significant value in designing novel immunotherapeutic agents, vaccines or protocols to combat viral reactivation in individuals with poor CD4 T cell function.

描述（由申请人提供）：潜伏疱疹病毒的重新激活对于免疫功能低下的个体（例如缺乏有效的 CD4 T 辅助细胞功能的艾滋病患者）来说是一个特殊问题。在缺乏 CD4 T 细胞的情况下动员残余免疫防御来对抗机会性感染的能力将为这些患者带来巨大的治疗优势。小鼠伽玛疱疹病毒 68 (MHV-68) 感染为研究持续性病毒感染的长期控制和测试潜在治疗剂控制病毒再激活的能力提供了有用的小动物模型。 MHV-68 是一种天然存在的啮齿动物病原体，与人类病原体 Epstein-Barr 病毒和卡波西肉瘤相关疱疹病毒密切相关。鼻内给药后，MHV-68 在小鼠肺部复制，并在 B 细胞和上皮细胞中建立潜伏感染。 CD4 T 细胞缺陷的小鼠可以清除病毒的初始攻击，但无法控制潜伏的病毒，病毒会在肺部重新激活。使用这种机会性感染的小鼠模型，我们表明用 CD40 激动性抗体治疗可以替代 CD4 T 细胞功能，并且在防止 CD4 T 细胞缺陷小鼠肺部潜伏 MHV-68 的重新激活方面非常有效。此外，我们的初步研究表明 CD8 T 细胞对于这种效果至关重要。然而，尚不清楚抗 CD40 治疗是否会增加 CD8 T 细胞功能或与 CD8 T 细胞联合发挥作用而不改变其活性。拟议的研究旨在剖析抗 CD40 抗体治疗防止 CD4 T 细胞缺陷小鼠病毒再激活的机制，如下所示：在目标 1 中，我们将确定 CD8 T 细胞的作用。在目标 2 中，我们将确定 CD40 阳性细胞（例如 B 细胞和树突状细胞）的作用。在目标 3 中，我们将确定反应的持续时间、所需治疗的次数和频率，以及抗 CD40 治疗是否能有效对抗持续的病毒再激活。这些研究中获得的信息对于设计新型免疫治疗剂、疫苗或方案以对抗 CD4 T 细胞功能较差的个体中的病毒再激活可能具有重要价值。