ANIMAL MODELS TO DESIGN AND EVALUATE IMPROVED VZV VACCINES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 研制有效的艾滋病疫苗仍然是艾滋病毒研究的最高优先事项之一。水痘-带状疱疹病毒（VZV）减毒活Oka疫苗可安全有效地预防水痘和带状疱疹，也有可能作为针对其他病原体（包括人类免疫缺陷病毒（HIV））的重组疫苗。猴水痘模型，利用猴水痘病毒（SVV），提供了一种方法来评估重组水痘疫苗的候选人。构建了表达猴免疫缺陷病毒（SIV）env和gag抗原的重组SVV（rSVV）疫苗病毒。检验的假设是，减毒rSVV-SIV活疫苗将在恒河猴中诱导针对SIV的免疫应答，并提供针对SIV攻击的保护。结果表明，rSVV-SIV疫苗接种在免疫的恒河猴中诱导低水平的中和抗体和对SIV的细胞免疫应答，并且在用致病性SIVmac 251-CX-1静脉内攻击后显著降低病毒载量。 作为先前研究的延续，本研究评价了其他免疫学参数，以进一步确定这些动物的保护相关性。使用CD 3、CD 4、CD 8、CD 28、CD 95和KI 67抗体进行流式细胞术以显示刺激的记忆淋巴细胞亚群的差异。 细胞内细胞因子测定测试了接种疫苗和攻击后PBMC的功能特征。 对免疫后14天、SIV攻毒当天和SIV攻毒后231天收获的冻存样品进行评价。 用SIV肽刺激样品，用CD 3、CD 4和CD 8表面标志物以及IL-2、TNF-A和IFN-g染色。结果显示，总体上，与SIV env特异性应答相比，实验性接种疫苗的动物具有更多的多功能CD 4+和CD 8 + T细胞SIV gag特异性应答。 CD 4辅助性T细胞中细胞增殖和抗原特异性多功能细胞因子应答的增加可能对控制接种疫苗和SIV攻击的猕猴中的病毒载量至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The development of an effective AIDS vaccine remains one of the highest priorities in HIV research. The live, attenuated varicella-zoster virus (VZV) Oka vaccine, safe and effective for prevention of chickenpox and zoster, also has potential as a recombinant vaccine against other pathogens, including human immunodeficiency virus (HIV). The simian varicella model, utilizing simian varicella virus (SVV), offers an approach to evaluate recombinant varicella vaccine candidates. Recombinant SVV (rSVV) vaccine viruses expressing simian immunodeficiency virus (SIV) env and gag antigens were constructed. The hypothesis tested was that a live, attenuated rSVV-SIV vaccine will induce immune responses against SIV in the rhesus macaques and provide protection against SIV challenge. The results demonstrated that rSVV-SIV vaccination induced low levels of neutralizing antibodies and cellular immune responses to SIV in immunized rhesus macaques and significantly reduced viral loads following intravenous challenge with pathogenic SIVmac251-CX-1. As a continuation of the previous study, this study evaluated additional immunological parameters to further define correlates of protection in these animals. Flow cytometry was conducted to show differences in stimulated memory lymphocyte subpopulations using CD3, CD4, CD8, CD28, CD95 and KI67 antibodies. Intracellular cellular cytokine assays tested functional characteristics of PBMCs following vaccination and challenge. Cryopreserved samples harvested 14 days following immunization, day of SIV challenge, and day 231 post SIV challenge were evaluated. Samples were stimulated with SIV peptides, stained with CD3, CD4, and CD8 surface markers and IL-2, TNF-A, and IFN-g. Results showed overall that experimental vaccinated animals have more polyfunctional CD4+ and CD8+ T cell SIVgag-specific responses compared with SIV env-specific responses. Increases in cellular proliferation and antigen specific polyfunctional cytokine responses in CD4 T helper cells may be crucial to control viral loads in vaccinated and SIV challenged macaques.