Optimization Of HIV Specific Immune Responses In Vivo

HIV 体内特异性免疫反应的优化

基本信息

批准号：
7964813
负责人：
ROBERT A SEDER
金额：
$ 164.19万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7964813
关键词：
Acquired Immunodeficiency Syndrome Address Adjuvant Agonist Animals Antibodies Antibody Formation Antigen-Presenting Cells Attenuated Attenuated Live Virus Vaccine Attenuated Vaccines CD8-Positive T-Lymphocytes CD8B1 gene Cause of Death Cells Cellular Immunity Cellular Immunology DEC-205 receptor DNA DNA Vaccines Data Dendritic Cells Dendritic cell activation Disease Drug Formulations Frequencies Gagging General Population Generations Goals HIV HIV vaccine Human Immune Immune response Immune system Immunity Immunization Infection Infection prevention Irrigation Laboratories Life Ligands Lung Maintenance Malaria Mediating Mediation Mus Pathway interactions Peripheral Blood Mononuclear Cell Play Poly I-C Primates Proteins Rodent Role SIV Safety T-Lymphocyte TLR3 gene TLR9 gene Toll-like receptors Treatment Protocols Tuberculosis Vaccination Vaccine Adjuvant Vaccines comparative gag Gene Products human TLR3 protein human TLR7 protein immunogenicity in vivo nonhuman primate pathogen plasmid DNA receptor expression recombinant virus vaccine research study response targeted delivery toll-like receptor 4 vaccine development vector vector-induced

项目摘要

Successful development of a vaccine against HIV will likely require the induction of both antibody and/or cellular immune responses sufficient to prevent infection or disease respectively following infectious challenge. While the induction of antibody responses for a variety of other infectious pathogens is readily achieved by a variety of vaccine formulations, live attenuated, recombinant viral vaccines or plasmid DNA vaccines only induce the induction of long-lived cellular immune responses, particularly CD8+ T cell responses. Moreover, since live attenuated HIV vaccines might be precluded from use due to safety concerns and DNA vaccines at present only induce modest CD8+ T cell responses in humans, there is an urgent need to develop ways to enhance the generation and maintenance of CD8+ T cell responses in humans in following immunization. This study focuses on how to optimize the magnitude and duration of CD8+ T cell responses following vaccination in rodents and primates using a variety of vaccine formulations. The data obtained over this past year have shown the following; 1. Prime-boost immunization with SIV Gag protein and TLR 3 or 7/8 ligands elicit potent T cell responses in non-human primates. Such responses were noted in both peripheral blood mononuclear cells and were much higher in the broncheoalveolar lavage. Upon boosting with rAd-5 SIV , CD8+ T cell responses were further enhanced. Animals were challenged with SIV Mac 251. These results show that a heterologous prime-boost immunization regimen using a protein and TLR ligand followed by rAd-5 induces potent T cell immunity. 2. Experiments in NHP have compared HIV Gag DNA versus HIV Gag protein+ Poly I:C as a prime prior to rAd-5 Gag as a boost. The data reveals that priming with DNA enhances both CD4 and CD8 responses after the rAd5 HIV Gag boost compared to rAd5 HIV Gag alone. By contrast, priming with HIV Gag protein+ Poly I:C enhanced the magnitude of CD4 responses following the rAd5 boost but not CD8 responses. Moreover, it was notable that DNA immunization but not protein + Poly I:C induced a small frequency of CD8 cells after the priming. Collectively these data suggest that priming for CD8+ T cells is critical if there is to be further expansion of such cells after the boost.

成功开发抗 HIV 疫苗可能需要诱导抗体和/或细胞免疫反应，足以分别预防感染攻击后的感染或疾病。虽然通过多种疫苗配方很容易实现针对多种其他感染性病原体的抗体反应的诱导，但减毒活重组病毒疫苗或质粒DNA疫苗只能诱导长效细胞免疫反应，特别是CD8+T细胞反应。此外，由于出于安全考虑，HIV减毒活疫苗可能被禁止使用，而DNA疫苗目前只能在人类中诱导适度的CD8+T细胞反应，因此迫切需要开发增强CD8+T细胞反应的产生和维持的方法在人类免疫接种后。本研究的重点是如何优化啮齿动物和灵长类动物使用各种疫苗配方接种疫苗后 CD8+ T 细胞反应的程度和持续时间。去年获得的数据表明： 1. 使用 SIV Gag 蛋白和 TLR 3 或 7/8 配体进行初免-加强免疫可在非人灵长类动物中引发有效的 T 细胞反应。这种反应在外周血单核细胞中均可见，并且在支气管肺泡灌洗液中更高。使用 rAd-5 SIV 加强后，CD8+ T 细胞反应进一步增强。用 SIV Mac 251 对动物进行攻击。这些结果表明，使用蛋白质和 TLR 配体，然后使用 rAd-5 的异源初免-加强免疫方案可诱导有效的 T 细胞免疫。 2. NHP 中的实验比较了 HIV Gag DNA 与 HIV Gag 蛋白+ Poly I:C 作为初免，然后 rAd-5 Gag 作为加强。数据显示，与单独使用 rAd5 HIV Gag 相比，在 rAd5 HIV Gag 加强后，用 DNA 引发可增强 CD4 和 CD8 反应。相比之下，用 HIV Gag 蛋白+ Poly I:C 引发可增强 rAd5 增强后 CD4 反应的强度，但不会增强 CD8 反应。此外，值得注意的是，DNA 免疫（而非蛋白质 + Poly I:C）在引发后诱导了少量 CD8 细胞。总的来说，这些数据表明，如果要在加强后进一步扩增 CD8+ T 细胞，则启动 CD8+ T 细胞至关重要。