Targeting mTOR to Enhance Immunogenicity and Efficacy of HIV Vaccines

靶向 mTOR 增强 HIV 疫苗的免疫原性和功效

基本信息

批准号：
8662365
负责人：
Rafi Ahmed
金额：
$ 60.32万
依托单位：
EMORY UNIVERSITY
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662365
关键词：
AIDS Vaccines AIDS/HIV problem ALVAC Acquired Immunodeficiency Syndrome Acute Address Adenoviruses Adherence Adjuvant Adverse effects Animals Antigens Antiviral Agents B-Lymphocytes Blood Blood Cells CCR5 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Count Cells Clinical Color Country Cytomegalovirus DNA Data Developed Countries Dose Down-Regulation Drug Targeting Frequencies Generations Genes Goals HIV HIV vaccine HIV/SIV vaccine Human Immune response Immunity Immunosuppressive Agents Individual Infection Interleukin-2 Latent Virus Lead Life Longevity Lymphocytic choriomeningitis virus Macaca Macaca mulatta Measures Memory Modeling Modified Vaccinia Virus Ankara Monitor Mus Organ Transplantation Pan Genus Pathway interactions Pharmaceutical Preparations Phase Plasma Production SIV SIV Vaccines Safety Signal Transduction Sirolimus Solutions Sorting - Cell Movement T cell differentiation T memory cell T-Lymphocyte TNFRSF5 gene TNFSF5 gene Testing Toxic effect Transplant Recipients Treatment Protocols Vaccinated Vaccination Vaccines Vaccinia virus Viral Viral Load result Virus Virus Diseases Virus Receptors Virus Replication Work Yellow fever virus base cost cytokine design drug resistant virus immunogenicity improved mTOR protein nonhuman primate novel novel strategies perforin protective efficacy receptor response vaccination strategy vaccine efficacy vaccine-induced immunity vector vaccine

项目摘要

Developing an effective HIV vaccine presents extraordinary challenges given the diversity of the virus and the need for inducing both T and B cell responses that can provide broad coverage, have the right functional qualities and are long-lasting. During the past decade there has been substantial progress in developing various vaccine vectors and prime-boost combinations for inducing effective responses against HIV. However, it is critical to improve upon these promising vaccine strategies and to design novel approaches for enhancing vaccine-induced immunity. We have recently made the unexpected and surprising observation that rapamycin, a drug that targets mTOR (mammalian target of rapamycin) and is commonly used in transplant recipients as an imunosuppressive agent, can actually enhance not only the magnitude but also the functional qualities of vaccine-induced virus specific memory T cells. This adjuvant effect of rapamycin was seen in both mice and in non-human primates. We have also shown that rapamycin acts intrinsically in antigen specific T cells and identified mTOR as a major regulator of memory T cell differentiation. Thus, our working hypothesis is that targeting mTOR presents a novel strategy of modulating both the quantity and quality of vaccine-induceti memory Tcells. In addition to regulating memory T cell differentiation rapamycin can also decrease expression of CCR5, the HIV co-receptor, on activated CD4 T cells. Here we propose to modulate the mTOR pathway during vaccination to enhance generation of highly polyfunctional virus-specific CDS T cells and to induce virus-specific CD4 T cells that are CCR5'¿ and are less susceptible to HIV/SIV infection. Taken together such a vaccination strategy may lead to enhanced control of HIV/SIV infection. To achieve our goal, we will investigate two important effects of rapamycin in rhesus macaques; 1) its safety and adjuvant effect in enhancing immunogenicity of AIDS vaccines and 2) its ability to enhance protection against a pathogenic SIV challenge.

鉴于病毒的多样性以及诱导的T和B细胞反应的需求，可以提供广泛的覆盖范围，具有正确的功能质量并且具有长期持久的诱导T和B细胞反应，因此开发有效的HIV疫苗会带来非凡的挑战。在过去的十年中，在开发各种疫苗载体和最大促进组合中为诱导艾滋病毒的有效反应而取得了重大进展。但是，对这些有希望的疫苗策略进行改进并设计新的方法来增强疫苗诱导的病毒至关重要。我们最近做出了一个意外且令人惊讶的观察结果，即雷帕霉素是一种靶向MTOR的药物（雷帕霉素的哺乳动物靶标），通常用于移植受者作为imnospressive剂，实际上不仅可以增强疫苗诱导的病毒特异性记忆T细胞的功能质量。雷帕霉素的这种辅助作用在小鼠和非人类隐私中都可以看到。我们还表明，雷帕霉素在抗原特异性T细胞中本质上起作用，并将MTOR确定为记忆T细胞分化的主要调节剂。这就是我们的工作假设是，针对MTOR提出了一种调节疫苗诱导的记忆TCELL的数量和质量的新策略。除了调节记忆T细胞分化外，雷帕霉素还可以降低活化的CD4 T细胞CCR5（HIV共受体的表达）。在这里，我们建议在疫苗期间调节MTOR途径，以增强高度多功能的病毒特异性CDS T细胞的产生，并诱导CCR5''病毒特异性CD4 T细胞，并且对HIV/SIV感染不太易感。将这种疫苗策略融合在一起可能会导致对HIV/SIV感染的控制。为了实现我们的目标，我们将研究雷帕霉素在恒河猕猴中的两个重要影响。 1）其安全性和可调节作用在增强艾滋病疫苗的免疫原性方面以及2）增强防御致病SIV挑战的能力。