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: 7294522
• 负责人: David T Evans
• 金额: $ 74.39万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294522
• 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; 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; Resistance; Route; SIV; Sexual Transmission; Site; Source; Staging; Surface; T-Lymphocyte; Testing; Treatment Protocols; Vaccinated; Vaccines; Vagina; Vesicular stomatitis Indiana virus; Viral Antigens; Viral Load result; Viral Proteins; Virion; Virus; Virus Replication; concept; insight; peripheral blood; pol genes; 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.

SIV的减毒活毒株仍能提供最可靠的保护，抵御致病性攻击病毒 在动物模型中。因此，更好地理解减毒病毒的保护机制， 为开发安全有效的艾滋病疫苗提供了至关重要的见解。我们已经开发了一个 一种生产SIV基因工程菌株的方法，所述菌株仅限于单轮感染， 一种非复制型艾滋病疫苗的方法。单周期SIV（scSIV）感染的细胞表达所有的病毒 除Pol外的基因产物释放不能完成后续轮的未成熟病毒颗粒 感染在以前的研究中，用scSIV免疫的恒河猴产生了不同的病毒特异性 免疫应答，并且在用野生型的静脉内攻击后能够部分地包含病毒载量 SIVmac239.最近，我们评估了反式互补对水泡性口炎的影响， 病毒糖蛋白（VSV G）和给药途径对病毒特异性T细胞应答的影响。单次 剂量的VSV G反式互补scSIV（VSV G scSIV），SIV特异性CD8+ T细胞应答更多 比先前接种非反式互补scSIV的动物中的应答高10倍以上。 病毒特异性CD8+ T细胞的表型分析也揭示了粘膜上皮细胞表达的差异。 归巢受体A4P7依赖于接种途径。在这里，我们建议使用VSV G scSIV作为 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。对于具体目标1，我们将检验以下假设： 用VSV G scSIV免疫决定了病毒特异性T细胞的粘膜归巢特性， 对SIVmac 239直肠内攻击的抗性。对于具体目标2，我们将检验以下假设： 引发位点影响病毒特异性T细胞应答的归巢， VSV G scSIV和针对SIVmac239阴道攻击的保护程度。对于具体目标3， 我们将检验用VSV G scSIV抗原性不同毒株的混合物免疫的假设 可以扩大病毒特异性免疫应答并增强对异源攻击的保护 病毒这些研究有助于本计划项目的总体目标，以确定 通过减毒疫苗株获得保护性免疫，并寻求有前途的新艾滋病疫苗概念。