Immunological control of a persistent viral infection

持续性病毒感染的免疫控制

• 批准号: 6861090
• 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/6861090
• 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）：潜伏疱疹病毒的再活化是免疫功能低下个体（如缺乏有效CD 4 T辅助细胞功能的AIDS患者）的一个特殊问题。在缺乏CD 4 T细胞的情况下动员残余免疫防御以对抗机会性感染的能力将对这些患者代表巨大的治疗优势。小鼠感染鼠γ疱疹病毒-68（MHV-68）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活化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EB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在小鼠肺中复制，并在B细胞和上皮中建立潜伏感染。CD 4 T细胞缺陷小鼠可以清除病毒的初始攻击，但无法控制潜伏病毒，后者在肺部重新激活。使用这种机会性感染的小鼠模型，我们发现用CD 40激动性抗体治疗可以替代CD 4 T细胞功能，并且在预防CD 4 T细胞缺陷小鼠肺中潜伏的MHV-68的再活化方面非常有效。此外，我们的初步研究表明，CD 8 T细胞是这种作用所必需的。然而，目前尚不清楚抗CD 40治疗是否会增加CD 8 T细胞功能或与CD 8 T细胞一起工作，而不改变其活性。所提出的研究旨在剖析抗CD 40抗体治疗防止CD 4 T细胞缺陷小鼠中病毒再活化的机制，如下：在目的1中，我们将确定CD 8 T细胞的作用。在目标2中，我们将确定CD 40阳性细胞（如B细胞和树突状细胞）的作用。在目标3中，我们将确定缓解的持续时间、所需治疗的次数和频率以及抗CD 40治疗是否对持续的病毒再激活有效。这些研究中获得的信息可能在设计新的免疫抑制剂、疫苗或方案以对抗CD 4 T细胞功能差的个体中的病毒再活化方面具有重要价值。