Effective Replicating Adenovirus-HIV Vaccines

有效复制腺病毒-HIV 疫苗

• 批准号: 9232080
• 负责人: MICHAEL A THOMAS
• 金额: $ 24.9万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232080
• 关键词: Acquired Immunodeficiency Syndrome; Adenovirus Protein; Adenovirus Vector; Adenoviruses; Adjuvant; Affect; Antibodies; Antibody titer measurement; Antigens; Attenuated Live Virus Vaccine; B-Lymphocytes; Biochemical; Biology; Carrying Capacities; Cell Communication; Cell Cycle; Cell Line; Cells; Cessation of life; Clinical; Cultured Cells; DNA Damage; Data; Development; Dose; Flow Cytometry; Gene Expression; Genes; Genetic; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; Health; Immune; Immune response; Immune system; Immunize; Lead; Link; M cell; Malignant Neoplasms; Masks; Measurable; Membrane Proteins; Methods; Microscopy; Molecular Biology; Mus; Open Reading Frames; Parents; Pathology; Play; Ploidies; Preventive vaccine; Process; Production; Reporting; Research; Safety; Signal Transduction; System; Techniques; Testing; Transgenes; Vaccines; Viral; Viral Genes; Viral Proteins; Virus; attributable mortality; cell type; cytokine; design; improved; pathogen; public health relevance; response; sobriety; targeted cancer therapy; transgene expression; vaccine delivery; vaccine efficacy; vector; vector vaccine; vector-induced

DESCRIPTION (provided by applicant): The sheer number of deaths attributable to human immunodeficiency virus (HIV)-induced acquired immunodeficiency syndrome (AIDS) is sobering, making the development of a preventative vaccine all the more urgent. Historically, the most effective vaccines are live-attenuated or inactivated pathogens. Safety concerns exclude these strategies in the case of HIV. In that regard both adenoviruses (Ad) that replicate (Ad�E3) and those that do not (Ad�E1�E3), represent a viable vaccine delivery method. In a recent comparison however, replicating Ad at lower doses induced better HIV transgene-specific immune responses than the non-replicating vector. Since the two vectors have the same surface proteins the advantage is most likely derived from virus-host cell interactions perpetuated by products of the viral genes that are severely muted in cells infected by the non-replicating vector. These virus-host cell interactions enhance transgene- specific immune responses and are herein termed the adjuvant quality of replicating Ad vectors. The goal of this proposed research is to develop a better understanding of the factors that influence the immune responses to the transgene within replicating Ad vaccine vectors. We test the global hypothesis that the adjuvant quality of replicating Ad is dependent on the products of the virus E1 and E4 genes. A rather curious discovery is that endoreduplication, a phenomenon that associates with DNA damage and genetic instability often observed in cancer, occurs in all Ad-infected cell types. Therefore the virus-host cell interactions that promote endoreduplication may be important to the virus pathology. If we can define the viral and cellular factors involved in this process we will improve our understanding of both adenoviral biology and cancer. Most importantly for replicating Ad-HIV vaccine vector is that, as in other systems, here too DNA damage/endoreduplication may also engage the immune system. Using biochemical, molecular biology, microscopy and flow cytometry techniques I will make and characterize various cell lines and gp120 transgene-bearing E1B55K/E3-deleted viruses additionally deleted of E4. These will be used in aim 1 to define the mechanism by which Ad induces endoreduplication in infected cells. In aim 2 I will determine if viruses that induce differing levels of endoreduplicaton elicit differing levels of Ad- and/or gp120-specific immune responses in immunized mice. The results of this study will inform the design and development of more effective replicating Ad-HIV vaccines.

描述（由适用提供）：可归因于人类免疫缺陷病毒（HIV）引起的后获得的免疫缺陷综合症（AIDS）的庞大死亡人数正在清醒，从而使预防性疫苗的发展变得更加紧迫。从历史上看，最有效的疫苗是现场直播或灭活的病原体。在艾滋病毒的情况下，安全问题排除了这些策略。在这方面，复制（AD e3）和不重复的腺病毒（AD）（AD e1e1‥E3）代表了一种可行的疫苗输送方法。然而，在最近的比较中，低剂量以比非复制载体相比，在较低剂量诱导的艾滋病毒转化特异性免疫反应更好。由于两个载体具有相同的表面蛋白，因此优势很可能来自病毒宿主细胞的相互作用，该病毒基因的产物永久存在，这些病毒基因的产物在被非复制载体感染的细胞中严重突变。这些病毒宿主宿主相互作用增强了转化特定的免疫反应，并在此称为复制AD载体的可调质量。这项拟议的研究的目的是更好地理解影响复制AD疫苗向量内转化的免疫反应的因素。我们测试了全球假设，即复制AD的可调节质量取决于病毒E1和E4基因的产物。一个相当奇怪的发现是，在所有AD感染的细胞类型中都发生了与DNA损伤和遗传不稳定性相关的现象。因此，促进内置的病毒宿主宿主相互作用对病毒病理可能很重要。如果我们可以定义此过程中涉及的病毒和细胞因素，我们将提高对腺病毒生物学和癌症的理解。对于复制AD-HIV疫苗载体的最重要的是，与其他系统一样，DNA损伤/内置也可能吸引免疫系统。使用生化，分子生物学，显微镜和流式细胞仪技术，我将制作并表征各种细胞系，而GP120转化带有E1B55K/E3删除的病毒也被E4删除。这些将用于AIM 1来定义AD在感染细胞中诱导内置的机制。在AIM 2中，我将确定影响差异化水平的病毒是否会引起免疫小鼠中AD-和/或GP120特异性免疫复杂的区分水平。这项研究的结果将为更有效的复制AD-HIV疫苗的设计和开发提供信息。

项目成果

Beyond Oncolytics: E1B55K-Deleted Adenovirus as a Vaccine Delivery Vector.

• DOI: 10.1371/journal.pone.0158505
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Thomas MA;Nyanhete T;Tuero I;Venzon D;Robert-Guroff M
• 通讯作者: Robert-Guroff M

E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses.

• DOI: 10.3390/vaccines10020295
• 发表时间: 2022-02-15
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Sangare K;Helmold Hait S;Moore M;Hogge C;Hoang T;Rahman MA;Venzon DJ;LaBranche C;Montefiori D;Robert-Guroff M;Thomas MA
• 通讯作者: Thomas MA