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

• 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
• 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

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.

据信，创新佐剂可能能够诱导更高滴度的广泛中和抗 HIV-1 抗体和更好的抗 HIV-1 T 细胞反应。我们建议探索一种通过使用抗腺苷能“辅佐剂”来提高抗艾滋病毒疫苗有效性的新机会。我们的抗腺苷能辅助佐剂是提高 cAMP 的 A2A 腺苷受体 (A2AR) 的合成或天然拮抗剂。我们假设这些辅助佐剂将通过防止细胞外腺苷对抗 HIV 免疫反应的抑制来增强抗 HIV 免疫。这是因为腺苷可能会抑制抗艾滋病病毒 T-B-和骨髓细胞通过 A2AR 发出信号。与项目 4 一起，我们将使用我们的辅助佐剂进一步提高独特的双功能纳米颗粒 HIV 免疫原（来自项目 1、2）的效果，这些免疫原展示天然结构和脂质包膜嵌入的 HIV-1 MPER 片段，并从颗粒核心释放 CD4 T 细胞表位。新型 HIV 免疫原与辅助佐剂一起，预计将增加 T 淋巴细胞和 B 淋巴细胞以及骨髓细胞的贡献，以释放其全部抗 HIV 能力 通过阻止 A2AR 的抑制作用。 在我们的目标中，我们将确定辅助佐剂是否会阻止先天性和适应性免疫系统细胞的抑制，以便它们充分表达其抗 HIV 疫苗诱导的活性。我们已经在几种传染病和癌症的体内模型中证明了 A2AR 拮抗剂可显着增强抗病原体和抗肿瘤免疫力。为了支持本文提出的研究的可行性，我们表明使用合成或天然 A2AR 拮抗剂治疗可导致显着增加 已接种HIV gp120加佐剂(明矾或MPLA)的小鼠中抗HIV gp120 IgG1、IgG2a和IgM的水平。这种共佐剂产生数量级增强的 gp120 特异性抗体的方法现在可以应用于引发广泛中和抗体的免疫原。