Mucosal immunity and heterologous protection induced by single-cycle SIV

单周期SIV诱导的粘膜免疫和异源保护

• 批准号: 8247066
• 负责人: Amitinder Kaur
• 金额: $ 71.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247066
• 关键词: AIDS Vaccines; Amino Acid Sequence; Animal Model; Animals; Antigenic Diversity; Attenuated; Attenuated Vaccines; Biopsy; CD8B1 gene; Cells; Complement; Data; Development; Dose; Engineering; Evaluation; Frequencies; Gastrointestinal tract structure; Genetic; Genetic Variation; Glycoproteins; Goals; Gut associated lymphoid tissue; HIV Infections; HIV-1; Home environment; Homing; Immune response; Immunity; Immunization; Individual; Infection; Intravenous; Life; Macaca; Macaca mulatta; Molecular Cloning; Mucosal Immunity; Preparation; Property; Regimen; Resistance; Route; SIV; Sexual Transmission; Site; Source; Staging; Surface; T cell response; T-Lymphocyte; Testing; Vaccinated; Vaccines; Vagina; Vesicular stomatitis Indiana virus; Viral Antigens; Viral Load result; Viral Proteins; Virion; Virus; Virus Replication; insight; peripheral blood; prevent; programs; receptor; rectal; response; subcutaneous; tool

Live, attenuated strains of SIV still afford the most reliable protection against pathogenic challenge viruses in animal models. Thus, a better understanding of the mechanisms of protection by attenuated viruses may provide insights crucial to the development of a safe and effective AIDS vaccine. We have developed an approach for producing genetically engineered strains of SIV that are limited to a single round of infection as a non-replicating AIDS vaccine approach. Single-cycle SIV (scSIV)-infected cells express all of the viral gene products except for Pol and release immature virus particles that cannot complete subsequent rounds of infection. In previous studies, rhesus macaques immunized with scSIV made diverse virus-specific immune responses and were able to partially contain viral loads after an intravenous challenge with wild-type SIVmac239. More recently, we evaluated the effects of trans-complementation with the vesicular stomatitis virus glycoprotein (VSV G) and the route of administration on virus-specific T cell responses. After a single dose of VSV G trans-complemented scSIV (VSV G scSIV), SIV-specific CD8+ T cell responses were more than 10-fold higher than previous responses in animals inoculated with non-trans-complemented scSIV. Phenotypic analysis of virus-specific CD8+ T cells also revealed differences in the expression of the mucosal homing receptor a4p7 depending on the route of inoculation. Here we propose to use VSV G scSIV as a tool to further investigate mechanisms of mucosal immunity and the extent of heterologous protection that may be achieved by this vaccine approach. For specific aim 1, we will test the hypothesis that the site of immunization with VSV G scSIV determines the mucosal homing properties of virus-specific T cells and resistance to an intrarectal challenge with SIVmac239. For specific aim 2, we will test the hypothesis that the site of priming influences the homing of virus-specific T cell responses expanded after a systemic boost with VSV G scSIV and the degree of protection against a vaginal challenge with SIVmac239. For specific aim 3, we will test the hypothesis that immunization with a mixture of antigenically divergent strains of VSV G scSIV can broaden virus-specific immune responses and enhance protection against a heterologous challenge virus. These studies contribute to the overall goals of this program project to define mechanisms of protective immunity by attenuated vaccine strains and to pursue promising new AIDS vaccine concepts.

现场，衰减的SIV菌株仍然可以提供最可靠的针对病原病毒的保护 在动物模型中。因此，更好地理解衰减病毒的保护机制可能 提供对安全有效艾滋病疫苗的开发至关重要的见解。我们已经开发了 生产基因工程菌株SIV的方法，该菌株仅限于单轮感染 一种非复制AIDS疫苗方法。单周期SIV（SCSIV）感染的细胞表达所有病毒 基因产物除了POL和释放未成熟的病毒颗粒，无法完成随后的回合 感染。在先前的研究中，用SCSIV免疫的恒河猕猴使病毒特异性多样 免疫反应，并能够在静脉内挑战后部分含有病毒载荷 SIVMAC239。最近，我们评估了与囊泡口腔炎的反式融合的影响 病毒糖蛋白（VSV G）和病毒特异性T细胞反应的给药途径。单曲之后 VSV G反式汇编SCSIV（VSV G SCSIV）的剂量，SIV特异性CD8+ T细胞反应更多 在接种非传播的SCSIV的动物中，动物中的反应比以前的反应高10倍。 病毒特异性CD8+ T细胞的表型分析也揭示了粘膜表达的差异 取决于接种途径，将受体A4P7归为A4P7。在这里，我们建议将VSV G SCSIV用作 进一步研究粘膜免疫机制和异源保护程度的工具 可以通过这种疫苗方法来实现。对于特定目标1，我们将检验以下假设 用VSV G SCSIV免疫确定病毒特异性T细胞和 SIVMAC239对直肠内挑战的抗性。对于特定目标2，我们将检验以下假设 启动部位会影响与全身性提升后，病毒特异性T细胞反应的归巢 VSV G SCSIV和针对SIVMAC239阴道挑战的保护程度。对于特定的目标3， 我们将检验以下假设，即VSV G SCSIV的抗原发散菌株的混合物免疫 可以扩大病毒特异性免疫反应并增强防止异源挑战的保护 病毒。这些研究为该计划项目的总体目标做出了贡献，以定义 通过减弱疫苗菌株并追求有希望的新艾滋病疫苗概念来保护性免疫。