Immunological control of a persistent viral infection

持续性病毒感染的免疫控制

• 批准号: 6849438
• 负责人: SALLY R. SARAWAR
• 金额: $ 13万
• 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/6849438
• 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)：潜伏的疱疹病毒的重新激活是免疫功能受损的人的一个特别问题，例如艾滋病患者，他们缺乏有效的CD4T辅助细胞功能。在没有CD4T细胞的情况下，动员剩余的免疫防御系统来对抗机会性感染的能力对这些患者来说是一个巨大的治疗优势。小鼠感染小鼠GHV-68(MHV-68)为研究持续病毒感染的长期控制和检测潜在的治疗药物控制病毒再激活的能力提供了一个有用的小动物模型。MHV-68是一种自然产生的啮齿动物病原体，与人类病原体Epstein-Barr病毒和卡波西肉瘤相关疱疹病毒关系密切。MHV-68病毒在小鼠鼻腔给药后在肺内复制，并在B细胞和上皮细胞中建立潜伏感染。CD4T细胞缺陷小鼠可以清除最初的病毒攻击，但无法控制潜伏病毒，潜伏病毒在肺部重新激活。利用这种小鼠机会性感染模型，我们证明了CD40激动型抗体可以替代CD4T细胞功能，并在防止CD4T细胞缺陷小鼠肺内潜伏的MHV-68重新激活方面非常有效。此外，我们的初步研究表明，CD8T细胞对这种作用是必不可少的。然而，目前尚不清楚抗CD40治疗是增加CD8T细胞的功能，还是与CD8T细胞协同工作，而不改变它们的活性。建议的研究旨在剖析抗CD40抗体治疗阻止CD4T细胞缺陷小鼠病毒重新激活的机制，如下：在目标1中，我们将确定CD8T细胞的作用。在目标2中，我们将确定CD40阳性细胞(如B细胞和树突状细胞)的作用。在目标3中，我们将确定应答的持续时间、所需治疗的次数和频率，以及抗CD40治疗是否对正在进行的病毒重新激活有效。这些研究中获得的信息可能对设计新的免疫治疗剂、疫苗或方案以对抗CD4T细胞功能低下的人的病毒重新激活具有重要价值。