Preventing the Hypoxia-Adenosinergic Inhibtion of Anti-HIV Immune Response

防止缺氧腺苷能抑制抗 HIV 免疫反应

基本信息

批准号：
8043237
负责人：
Michail Sitkovsky
金额：
$ 28.45万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8043237
关键词：
Acquired Immunodeficiency Syndrome Acute Adenosine Adenosine A2A Receptor Adenosine A2B Receptor Adenosine Kinase Adjuvant Affinity Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigens Attenuated B-Lymphocytes Binding CD4 Positive T Lymphocytes Caffeine Cancer Vaccines Cell Maturation Cells Clinical Communicable Diseases Coupled Cyclic AMP Data Development Effectiveness Enzymes Epidemic Generations Genetic Goals HIV HIV Antibodies HIV Envelope Protein gp120 HIV Infections HIV vaccine HIV-1 Human Hypoxia Immune Immune response Immune system Immunity Immunoglobulin Class Switching Immunoglobulin M Immunosuppression Immunosuppressive Agents Infection Lipids MHC Class II Genes Malignant Neoplasms Mediating Medical Membrane Lipids Methods Modeling Mus Myeloid Cells Normal tissue morphology Nucleosome Core Particle Pathway interactions Patients Peptides Pharmaceutical Preparations Physiological Production Proteins Public Health Publishing Purinergic P1 Receptors Receptor Signaling Recombinant Vaccines Regulatory T-Lymphocyte Role Serum Signal Transduction Structure T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Tissues Translating Translations Tumor Immunity Vaccinated Vaccination Vaccine Therapy aluminum sulfate base cell mediated immune response cytokine drug testing extracellular improved in vivo Model innovation nanoparticle neutralizing antibody novel novel strategies overexpression pathogen plasma cell development prevent receptor function response vaccination strategy vaccine-induced immunity

项目摘要

It is believed that innovative adjuvants might be capable of inducing higher titers of broadly neutralizing anti-HIV-1 antibodies and better anti-HIV-1 T-cell responses. We propose to explore a novel opportunity to improve the effectiveness of anti-HIV vaccines by using anti-adenosinergic "co-adjuvants". Our antiadenosinergic co-adjuvants are synthetic or natural antagonists of cAMP-elevating A2A adenosine receptor (A2AR). We hypothesize that these co-adjuvants will enhance anti-HIV immunity by preventing the inhibition of anti-HIV immune response by extracellular adenosine. This is because adenosine may inhibit the anti-HIV T- B- and myeloid cells by signaling via their A2AR. Together with Project 4, we will use our co-adjuvants to further improve the effects of unique bifunctional nanoparticle HIV immunogens (from Projects 1, 2) that display the natively-structured and lipid envelope-embedded HIV-1 MPER segment and release CD4 T cell epitopes from the particle core. The novel HIV immunogens, together with co-adjuvants, are expected to increase the contribution of T- and B-lymphocytes and myeloid cells to unleash their full anti-HIV capacities by preventing their inhibition by A2AR. In our aims, we will determine whether co-adjuvants will prevent inhibition of cells of innate and adaptive immune systems so they will fully express their anti-HIV vaccine-induced activities. We have already demonstrated the strong enhancement of anti-pathogen- and anti-tumor immunity by A2AR antagonists in several in vivo models of infectious diseases and cancer. In support ofthe feasibility ofthe studies proposed here, we show that treatment with synthetic or natural A2AR antagonists resulted in significantly increased levels of anti-HIV gpl20 IgGI, lgG2a and IgM in mice that have been vaccinated with HIV gpl20 plus adjuvant (Alum or MPLA). This method of co-adjuvanting to generate an order of magnitude augmentation of gp120-specific antibody can now be applied to immunogens eliciting broadly neutralizing antibodies.

据认为，创新的佐剂可能能够诱导更高的中和抗HIV-1抗体和更好的抗HIV-1 T细胞反应的较高的滴度。我们建议通过使用抗腺苷能“共助剂”来探索一种新的机会，以提高抗HIV疫苗的有效性。我们的抗毒素能共助剂是营地A2A腺苷受体（A2AR）的合成或天然拮抗剂。我们假设这些共辅助因素将通过防止细胞外腺苷抑制抗HIV免疫反应来增强抗HIV免疫。这是因为腺苷可以抑制抗HIV T-B-和髓样细胞通过其A2AR发出信号。与项目4一起，我们将使用共加旋进一步改善独特的双功能纳米颗粒HIV免疫原子（来自项目1，2），这些纳米颗粒hiv免疫剂（来自项目1，2）显示了固l式结构化和脂质包膜内的HIV-1 MPER段和释放的CD4 T细胞表位。新型的HIV免疫原子以及共辅助剂有望增加T-和B淋巴细胞和髓样细胞的贡献，以释放其全抗HIV能力通过防止其抑制A2AR。在我们的目标中，我们将确定共助剂是否会防止对先天和适应性免疫系统的细胞抑制，以便它们将充分表达其抗HIV疫苗诱导的活性。我们已经证明了A2AR拮抗剂在几种传染病和癌症模型中，A2AR拮抗剂对抗病原体和抗肿瘤免疫的强烈增强。为了支持此处提出的研究的可行性，我们表明使用合成或天然A2AR拮抗剂的治疗显着增加抗HIV GPL20 IgGI，LGG2A和IgM的水平已接种HIV GPL20加辅助（校友或MPLA）。现在可以将这种共同辅助的方法生成GP120特异性抗体的数量级增强级的方法，可应用于引起广泛中和抗体的免疫原子。