Mucosal immunity and heterologous protection induced by single-cycle SIV

活的、减毒的SIV毒株仍然对致病挑战病毒提供最可靠的保护 在动物模型中。因此，更好地理解减毒病毒的保护机制可能 提供对开发安全有效的艾滋病疫苗至关重要的见解。我们已经开发出一种 生产仅限于单轮感染的SIV基因工程菌株的方法 一种非复制的艾滋病疫苗接种方法。单周期SIV(ScSIV)感染的细胞表达所有的病毒 除Pol和Pol外的基因产品释放不成熟的病毒颗粒，无法完成后续轮次 感染的可能性。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 在对野生型病毒进行静脉攻击后，免疫反应和部分控制病毒载量 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细胞反应的影响。在一首单曲之后 VSV G反式互补单链SIV(VSV G ScSIV)剂量、SIV特异性CD8+T细胞应答较多 在接种非反式互补scSIV的动物中，反应比以前高出10倍以上。 对病毒特异性CD8+T细胞的表型分析也显示了粘膜表达的差异 归巢受体a4p7取决于接种途径。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种免疫保护程度的工具 可以通过这种疫苗方法来实现。对于特定的目标1，我们将检验以下假设 VSV G scSIV免疫决定病毒特异性T细胞的粘膜归巢特性 抵抗SIVmac239直肠内挑战。对于特定的目标2，我们将测试假设 启动部位影响全身增强后病毒特异性T细胞反应的归巢 使用SIVmac239，VSV G scSIV和针对阴道挑战的保护程度。对于特定的目标3， 我们将检验这样一种假设，即用抗原性不同的VSV G scSIV混合毒株免疫 可以扩大病毒特异性免疫反应并增强对异源挑战的保护 病毒。这些研究有助于该计划项目的总体目标，以确定 通过减毒疫苗毒株进行保护性免疫，并寻求有前途的艾滋病疫苗新概念。

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.