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抗体和/或细胞免疫反应，足以防止感染挑战后分别预防感染或疾病。尽管多种疫苗制剂可以轻松地诱导各种其他感染性病原体的抗体反应，但仅诱导长期寿命的细胞免疫反应，尤其是CD8+ T细胞反应。此外，由于由于安全问题和DNA疫苗目前仅诱导人类中的适度CD8+ T细胞反应，因此可能无法使用活死的HIV疫苗，因此迫切需要开发方法来增强人类免疫后人类中CD8+ T细胞反应的产生和维持。这项研究的重点是如何使用多种疫苗配方在啮齿动物和灵长类动物接种后优化CD8+ T细胞反应的幅度和持续时间。过去一年获得的数据显示了以下内容； 1。用SIV GAG蛋白和TLR 3或7/8配体引起非人类灵长类动物的有效T细胞反应的原始促进免疫。在两个外周血单核细胞中都注意到了这种反应，在支气管肺泡灌洗中都高得多。用RAD-5 SIV增强后，CD8+ T细胞反应进一步增强。 SIV MAC 251挑战了动物。这些结果表明，使用蛋白质和TLR配体的异源原始促进免疫治疗方案，然后rad-5诱导有效的T细胞免疫。 2。在NHP中进行的实验已将HIV GAG DNA与HIV GAG蛋白+ Poly I：C作为Rad-5 GAG之前的素数为素数，作为增强。数据表明，与仅RAD5 HIV GAG相比，使用DNA启动可以增强CD4和CD8反应。相比之下，用HIV GAG蛋白+ Poly I：C启动启动后，在RAD5增强后增强了CD4响应的大小，但不是CD8响应。此外，值得注意的是，DNA免疫，而不是蛋白质 + Poly I：C诱导启动后CD8细胞的频率很小。总的来说，这些数据表明，如果在增强后要进一步扩展此类细胞，则CD8+ T细胞的启动至关重要。