Innate Restriction Factor Modulation of Retrovirus-specific Humoral Immunity

逆转录病毒特异性体液免疫的先天限制因子调节

基本信息

批准号：
8074970
负责人：
Mario Luis Santiago
金额：
$ 70.96万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074970
关键词：
26S proteasome Acute Acute Erythroblastic Leukemia Anti-Retroviral Agents Antibodies Antibody Formation Antigens Attenuated B-Cell Development B-Lymphocytes Binding Binding Sites Biochemical Biology CD4 Positive T Lymphocytes Cell physiology Cells Chromosomes, Human, Pair 15 Chromosomes, Human, Pair 22 Complex Data Development Engineering Enzymes Epitopes Evaluation Event Evolution Family member Friend Murine Leukemia Virus Friends Gastrointestinal tract structure Genes Genetic Glycoproteins Goals HIV HIV Budding HIV vaccine HIV-1 Health Priorities Homologous Gene Host resistance Human Humoral Immunities Immune response Immunoglobulin A Immunology Individual Infection Interferon Type I Knowledge Lentivirus Infections Life Cycle Stages Link Macaca Macaca mulatta Maps Mediating Modeling Molecular Molecular Evolution Molecular Virology Monitor Monkeys Mucosal Immune Responses Mus Natural Immunity Pathogenesis Phenotype Primate Lentiviruses Property Proteins Recovery Regulation Resistance Retroviridae Retroviridae Infections Role SIV Sampling Science Sexual Transmission Specificity Splenomegaly Structural Models Subfamily lentivirinae System T-Cell Depletion Testing Time TimeLine Urine Vaccine Design Vaccine Research Vaccines Viral Viral Physiology Viremia Virion Virus Virus Diseases Virus-like particle arm attenuation cytokine deoxycytidine deaminase fascinate global health improved in vivo innovation insight mouse model neutralizing antibody particle prevent resistance mechanism resistant strain response vaccine development virus development

项目摘要

DESCRIPTION (provided by applicant): Developing an HIV-1 vaccine that elicits a potent neutralizing antibody response is a global health priority, but this response is not associated with protection in natural infections. Identifying mechanisms to improve humoral immunity against HIV-1 may therefore critically guide vaccine development efforts. In contrast to HIV- 1 infection in humans or SIV infection in macaques, resistant strains of mice infected with Friend retrovirus (FV) develop neutralizing antibody responses that are critical for recovery. Furthermore, vaccine protection against FV is dependent on neutralizing antibody responses. Interestingly, the FV-specific neutralizing antibody response is significantly influenced by a key host gene, Rfv3. We recently identified Rfv3 as Apobec3, a deoxycytidine deaminase with broad activity against retroviruses, including HIV-1 (Santiago ML et al. 2008. Science 321:1343-46). Apobec3 restricts retroviruses in the next target cell, facilitating the release of fusion- competent, non-infectious virions that may function as "natural B-cell immunogens" in vivo. Unraveling the fascinating link between Apobec3 and the humoral arm of the immune response may therefore have important implications for HIV-1 vaccine development. Our overall objective is to probe the Apobec3-neutralizing antibody link in two pathogenic retrovirus systems. In Specific Aim 1, we propose to determine the underlying mechanism for the Apobec3/Rfv3 phenotype in the FV murine model. This would involve monitoring virus- specific B cell development, interrogating the role of Type I Interferon regulation of Apobec3 in vivo, and assessing the molecular properties that distinguish a protective versus a non-protective antibody response. Notably, primate lentiviruses antagonize the simian and human homologues of Apobec3 through the action of Vif. Thus, attenuating Vif function may rescue Apobec3 and improve neutralizing antibody responses. In Specific Aim 2, we propose to determine the impact of Vif attenuation on humoral immunity against SIV infection. This would involve comparing Apobec3 function, viral evolution, B cell phenotypes and neutralizing antibody development in rhesus macaques infected with wild-type, Vif-attenuated and Nef-deleted SIVmac239. SIVmac239 rarely elicits a strong neutralizing antibody response and triggers rapid and extensive CD4+ T cell depletion in the gastrointestinal tract, likely weakening mucosal immune responses. By analyzing sequential fecal and urine samples, we will test whether enabling Apobec3 function will improve virus-specific mucosal IgA responses. If the Apobec3/Rfv3 phenotype in mice extends to primate lentivirus infections, the molecular properties of induced systemic and mucosal virus-specific antibodies may yield crucial and innovative insights for HIV-1 vaccine design. Detailed insights on the interplay between Apobec3-mediated innate immunity and retrovirus-specific neutralizing antibody development may critically guide the construction and evaluation of HIV vaccines.

描述（由申请人提供）：开发一种能引发有效中和抗体反应的 HIV-1 疫苗是全球健康的优先事项，但这种反应与自然感染的保护无关。因此，确定提高针对 HIV-1 的体液免疫的机制可能对疫苗开发工作具有重要指导作用。与人类的 HIV-1 感染或猕猴的 SIV 感染不同，感染 Friend 逆转录病毒 (FV) 的小鼠的耐药株会产生对恢复至关重要的中和抗体反应。此外，针对 FV 的疫苗保护依赖于中和抗体反应。有趣的是，FV 特异性中和抗体反应受到关键宿主基因 Rfv3 的显着影响。我们最近将 Rfv3 鉴定为 Apobec3，一种脱氧胞苷脱氨酶，具有广泛的抗逆转录病毒活性，包括 HIV-1（Santiago ML et al. 2008. Science 321:1343-46）。 Apobec3 限制下一个靶细胞中的逆转录病毒，促进具有融合能力的非感染性病毒体的释放，这些病毒体在体内可充当“天然 B 细胞免疫原”。因此，解开 Apobec3 与免疫反应的体液臂之间的迷人联系可能对 HIV-1 疫苗的开发具有重要意义。我们的总体目标是探索两个致病性逆转录病毒系统中 Apobec3 中和抗体的联系。在具体目标 1 中，我们建议确定 FV 小鼠模型中 Apobec3/Rfv3 表型的基本机制。这将涉及监测病毒特异性 B 细胞的发育、探究 I 型干扰素在体内对 Apobec3 的调节作用，以及评估区分保护性抗体反应和非保护性抗体反应的分子特性。值得注意的是，灵长类慢病毒通过 Vif 的作用对抗 Apobec3 的猿猴和人类同源物。因此，减弱 Vif 功能可能会拯救 Apobec3 并改善中和抗体反应。在具体目标 2 中，我们建议确定 Vif 减弱对 SIV 感染体液免疫的影响。这将涉及比较感染野生型、Vif 减毒和 Nef 缺失 SIVmac239 的恒河猴中的 Apobec3 功能、病毒进化、B 细胞表型和中和抗体发育。 SIVmac239 很少引起强烈的中和抗体反应，并引发胃肠道中快速和广泛的 CD4+ T 细胞耗竭，可能会削弱粘膜免疫反应。通过分析连续的粪便和尿液样本，我们将测试启用 Apobec3 功能是否会改善病毒特异性粘膜 IgA 反应。如果小鼠中的 Apobec3/Rfv3 表型延伸到灵长类慢病毒感染，那么诱导的全身和粘膜病毒特异性抗体的分子特性可能会为 HIV-1 疫苗设计提供重要且创新的见解。关于 Apobec3 介导的先天免疫和逆转录病毒特异性中和抗体发展之间相互作用的详细见解可能会为 HIV 疫苗的构建和评估提供重要指导。