Immunological control of a persistent viral infection

持续性病毒感染的免疫控制

• 批准号: 6850009
• 负责人: SALLY R. SARAWAR
• 金额: $ 40.95万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850009
• 关键词: B lymphocyte; CD40 molecule; CD95 molecule; Gammaherpesvirinae; Herpesviridae disease; antibody; chemoprevention; cytokine; cytolysins; cytotoxic T lymphocyte; dendritic cells; disease /disorder model; genetically modified animals; immunotherapy; laboratory mouse; latent virus infection; nonhuman therapy evaluation; opportunistic infections; passive immunization; pore forming protein; tumor necrosis factor alpha

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）：在免疫功能低下的个体（例如AIDS患者）中，潜在的疱疹病毒的重新激活是缺乏有效CD4 T辅助细胞功能的特殊问题。在没有CD4 T细胞的情况下，动员残留免疫防御能够对抗机会性感染的能力将代表这些患者的巨大治疗优势。用鼠γ瘤病毒-68（MHV-68）感染小鼠，提供了一种有用的小动物模型，用于研究对持续性病毒感染的长期控制，并测试潜在治疗剂控制病毒重新激活的能力。 MHV-68是一种天然发生的啮齿动物病原体，与人类病原体Epstein-Barr病毒和Kaposi与肉瘤相关的疱疹病毒密切相关。 MHV-68在鼻内给药后在小鼠的肺中复制，并在B细胞和上皮中建立潜在的感染。 CD4 T细胞缺陷型小鼠可以清除病毒的初始挑战，但无法控制在肺部重新激活的潜在病毒。使用这种机会性感染的小鼠模型，我们表明用CD40激动抗体的治疗可以代替CD4 T细胞功能，并且在防止CD4 T细胞缺陷型小鼠肺中潜在MHV-68的重新激活非常有效。此外，我们的初步研究表明，CD8 T细胞对于这种作用至关重要。但是，尚不清楚抗CD40治疗是否会增加CD8 T细胞功能或与CD8 T细胞结合使用，而无需改变其活性。拟议的研究旨在剖析抗CD40抗体治疗阻止CD4 T细胞缺陷小鼠病毒再活化的机制，如下所示：在AIM 1中，我们将确定CD8 T细胞的作用。在AIM 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AIM 3中，我们将确定反应的持续时间，所需治疗的数量和频率以及抗CD40治疗是否有效，可抗持续的病毒重新激活。在这些研究中获得的信息在设计新型的免疫治疗剂，疫苗或方案以对抗CD4 T细胞功能较差的个体的病毒重新激活的新型信息可能具有重要价值。