Immunogenicity of HSV Amplicons in Rhesus Macaques

恒河猴中 HSV 扩增子的免疫原性

• 批准号: 6656018
• 负责人: DAVID W MARTIN
• 金额: $ 25.2万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6656018
• 关键词: AIDS vaccines; Alphaherpesvirinae; Macaca mulatta; antigen antibody reaction; biotechnology; gag protein; gene delivery system; humoral immunity; immunity; immunoregulation; leukocyte activation /transformation; lymphocyte proliferation; mucosal immunity; natural killer cells; simian immunodeficiency virus; vaccine development; virus antigen; virus morphology

DESCRIPTION (provided by applicant): The best strategy for preventing the continuing spread of infection with the human immunodeficiency virus (HIV) involves the development of an effective vaccine. Herpes simplex virus (HSV) amplicons represent a novel and promising strategy for vaccine development. HSV amplicons maintain several advantages as a vaccine strategy. First, HSV amplicons cannot cause any infectious disease. Second, HSV amplicons have a wide host cell tropism and are able to efficiently enter multiple cell types including mucosal cells. Third, HSV amplicons have a large coding capacity, which allows for the development of vectors that could encode multiple antigens and/or immunostimulatory gene products. Finally, HSV amplicons do not contain the immunomodulatory genes that are a part of replication-defective or attenuated HSV delivery systems. Previous studies with HSV amplicons have been performed in small animal model systems. However, the immunogenicity of these amplicons has never been tested in a non-human primate model system. The studies described in this proposal will determine if HSV amplicons can elicit a significant immune response in the rhesus macaque. Specifically, rhesus macaques will be inoculated via an intramuscular route with HSV amplicons that express the SIVmac239 gag gene product or by control amplicons that do not express any SIV gene product. The cellular immune response to Gag will be followed through analysis of CD4+ and CD8+ T cell responses, tetramer staining, and antigen-specific cytokine production. The humoral response will be determined by analysis of both serum and mucosal immunity. Finally, the innate immune response will be determined through analysis of both natural killer cells and by performing longitudinal studies of changes in lymphocyte proliferation and activation. Successful completion of these studies will allow for efficacy trials to be initiated in the SIV model system. Future studies may be extended to utilize HSV as a vaccine delivery system to prevent HIV infection of humans. In addition, the successful completion of these studies will have a significant impact on the continued development of HSV amplicons as gene and cancer therapy vectors.

描述（由申请人提供）：预防人类免疫缺陷病毒（HIV）感染持续传播的最佳策略包括开发有效的疫苗。 单纯疱疹病毒（HSV）扩增子代表了一种新的和有前途的疫苗开发策略。 HSV扩增子作为疫苗策略保持几个优点。 首先，HSV扩增子不会引起任何传染病。 其次，HSV扩增子具有广泛的宿主细胞向性，并且能够有效地进入包括粘膜细胞在内的多种细胞类型。 第三，HSV扩增子具有大的编码能力，这允许开发可编码多种抗原和/或免疫刺激基因产物的载体。 最后，HSV扩增子不含有作为复制缺陷型或减毒HSV递送系统的一部分的免疫调节基因。 以前用HSV扩增子的研究已经在小动物模型系统中进行。 然而，这些扩增子的免疫原性从未在非人灵长类动物模型系统中进行过测试。 本提案中描述的研究将确定HSV扩增子是否可以在恒河猴中引起显著的免疫应答。 具体而言，将通过肌内途径用表达SIVmac 239 gag基因产物的HSV扩增子或不表达任何SIV基因产物的对照扩增子接种恒河猴。 将通过分析CD 4+和CD 8 + T细胞应答、四聚体染色和抗原特异性细胞因子产生来跟踪对Gag的细胞免疫应答。 将通过分析血清和粘膜免疫来确定体液应答。 最后，通过分析自然杀伤细胞和进行淋巴细胞增殖和活化变化的纵向研究来确定先天免疫应答。 这些研究的成功完成将允许在SIV模型系统中启动疗效试验。 未来的研究可能会扩展到利用HSV作为疫苗递送系统来预防人类HIV感染。 此外，这些研究的成功完成将对HSV扩增子作为基因和癌症治疗载体的持续发展产生重大影响。