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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.

成功开发针对HIV的疫苗可能需要诱导足以分别预防感染性攻击后的感染或疾病的抗体和/或细胞免疫应答。虽然通过多种疫苗制剂容易实现对多种其它感染性病原体的抗体应答的诱导，但是减毒活重组病毒疫苗或质粒DNA疫苗仅诱导长寿命细胞免疫应答的诱导，特别是CD 8 + T细胞应答。此外，由于减毒活HIV疫苗可能由于安全性问题而被排除使用，并且DNA疫苗目前仅在人体中诱导适度的CD 8 + T细胞应答，因此迫切需要开发在免疫后增强人体中CD 8 + T细胞应答的产生和维持的方法。这项研究的重点是如何优化CD 8 + T细胞反应的幅度和持续时间后，在啮齿动物和灵长类动物使用各种疫苗配方接种。过去一年获得的数据表明： 1.用SIV Gag蛋白和TLR 3或7/8配体的初免-加强免疫在非人灵长类动物中引发有效的T细胞应答。在外周血单核细胞中均观察到这种反应，并且在支气管肺泡灌洗中更高。在用rAd-5 SIV加强后，CD 8 + T细胞应答进一步增强。用SIV Mac 251攻击动物。这些结果表明，使用蛋白质和TLR配体，随后使用rAd-5的异源初免-加强免疫方案诱导有效的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，与单独的rAd 5 HIV Gag相比，用DNA引发增强了rAd 5 HIV Gag加强后的CD 4和CD 8应答。相比之下，用HIV Gag蛋白+ Poly I：C引发增强了rAd 5加强后的CD 4应答的幅度，但不增强CD 8应答。此外，值得注意的是，DNA免疫而不是蛋白+ Poly I：C在引发后诱导了小频率的CD 8细胞。总的来说，这些数据表明，如果在加强免疫后要进一步扩增CD 8 + T细胞，那么对CD 8 + T细胞的引发是至关重要的。