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

• 批准号: 7988826
• 负责人: Mario Luis Santiago
• 金额: $ 75.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/7988826
• 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; Disease; 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; HIV-1 vaccine; 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-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; vif Gene Products; virus development

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）： 开发引起有效中和抗体反应的HIV-1疫苗是全球健康的优先级，但是这种反应与自然感染的保护无关。因此，确定改善对HIV-1的体液免疫力的机制可能会严重指导疫苗开发工作。与猕猴中的人类或SIV感染中的HIV-1感染相反，感染朋友逆转录病毒（FV）的小鼠抗性菌株会产生对恢复至关重要的中和抗体反应。此外，针对FV的疫苗保护取决于中和抗体反应。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，这是一种脱氧胞苷脱氨酶，具有广泛活性的逆转录病毒，包括HIV-1（Santiago Ml等，2008。Science321：1343-46）。 APOBEC3限制了下一个靶细胞中的逆转录病毒，从而促进了融合能力的，非感染的病毒体的释放，这些病毒体可能充当体内“天然B细胞免疫原”。因此，揭开Apobec3与免疫反应的体液部门之间的迷人联系可能对HIV-1疫苗的发育具有重要意义。我们的总体目标是在两个致病性逆转录病毒系统中探测APOBEC3中和抗体链接。在特定目标1中，我们建议确定FV鼠模型中APOBEC3/RFV3表型的基本机制。这将涉及监测特定于病毒的B细胞发育，询问体内APOBEC3的I型干扰素调节的作用，并评估区分保护性与非保护抗体反应的分子特性。值得注意的是，灵长类动理通过VIF的作用拮抗Apobec3的猿猴和人类同源物。因此，衰减VIF功能可以挽救APOBEC3并改善中和抗体反应。在特定目标2中，我们建议确定VIF衰减对体液免疫对SIV感染的影响。这将涉及比较APOBEC3功能，病毒进化，B细胞表型和中和抗体发育中的恒河猕猴感染了野生型，vif插入和NEF骨骼损坏的SIVMAC239。 SIVMAC239很少引起强烈的中和抗体反应，并触发胃肠道中的快速而广泛的CD4+ T细胞耗竭，可能会削弱粘膜免疫反应。通过分析顺序粪便和尿液样品，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表型延伸至灵长类动病毒感染，则诱导的全身和粘膜特异性抗体的分子特性可能会产生HIV-1疫苗设计的关键和创新见解。对APOBEC3介导的先天免疫力与逆转录病毒特异性中和抗体发育之间相互作用的详细见解可以严格指导HIV疫苗的构建和评估。