Conserved Elements Therapeutic DNA Vaccine for HIV

HIV 保守元件治疗性 DNA 疫苗

• 批准号: 8890105
• 负责人: Deborah H. Fuller
• 金额: $ 98.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890105
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Animals; Antigens; Avidity; Blood; CD8B1 gene; Combined Vaccines; Conserved Sequence; Control Animal; DNA; DNA Vaccines; Disease; Drug Combinations; Elements; Epidermis; Epitopes; Evolution; Exhibits; Failure; Frequencies; Gagging; Goals; Gut associated lymphoid tissue; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Health; Highly Active Antiretroviral Therapy; Immune; Immune Targeting; Immune response; Immunization; Indium; Infection; Inflammatory disease of the intestine; Lead; Macaca; Macaca mulatta; Measures; Mediating; Methods; Mutate; Mutation; Patients; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Proteins; Regimen; Residual state; Role; SIV; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Vaccinated; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viremia; Virus; antiretroviral therapy; cost; design; fitness; frontier; gene gun; improved; novel; novel therapeutics; prevent; prototype; response; therapeutic DNA; therapeutic vaccine

DESCRIPTION (provided by applicant): Our previous studies have shown that therapeutic DNA vaccine induction of mucosal responses correlated with significant reduction of virus in the gut of SIV-infected macaques despite the use of a suboptimal ART regimen. This vaccine stimulated T cell responses that suppressed virus to low/undetectable levels and afforded a durable "functional cure" in ~50% of the animals after stopping ART. We propose here to make therapeutic vaccination even more effective by 1) using a more potent combination of drugs (cART) to maximize the effects of the vaccine, 2) using a mucosal adjuvant (LT) to target immune responses to residual virus in gut associated lymphoid tissue, and 3) use of a novel SIV conserved elements (CE) DNA vaccine to focus T cell responses against highly conserved viral sequences that if mutated will impose greater fitness cost. Our overarching hypothesis is that vaccine-induced functional cure is mediated by strong mucosal CD8 responses, and that focusing these responses to the gut in maximally suppressed infections and against more conserved epitopes, which suppress a wider range of possible viral variants and select for more fitness-costing escape mutations, will maximally disable the ability of residual viruses to emerge from the latent reservoir after stopping cART. Operationally, using optimized cART and mucosal targeting we will compare a traditional whole antigen and a CE DNA vaccine for the ability to increase the frequency and strength of mucosal and systemic CD8 responses against conserved viral sequences, and for their impact on viral evolution and fitness, and determine the role of these factors in a functional cure. Our specific aims are to: 1) Determine therapeutic efficacy of an LT-adjuvanted traditional SIV DNA vaccine expressing whole antigens when used with more potent cART. 2) Determine if an SIV CE immunogen will improve therapeutic efficacy. 3) Define immune and virological mechanisms underlying functional cures. Through the proposed studies we will define the virological and immune profile of a vaccine-induced functional cure and determine the feasibility of a novel CE DNA vaccine to induce a functional cure of SIV infection.

描述（由申请人提供）： 我们之前的研究表明，尽管使用了次优的 ART 方案，但治疗性 DNA 疫苗诱导的粘膜反应与感染 SIV 的猕猴肠道中病毒的显着减少相关。这种疫苗刺激 T 细胞反应，将病毒抑制到低/不可检测的水平，并在停止 ART 后为约 50% 的动物提供持久的“功能性治愈”。我们在此建议通过以下方式使治疗性疫苗接种更加有效：1) 使用更有效的药物组合 (cART) 来最大限度地发挥疫苗的效果，2) 使用粘膜佐剂 (LT) 来针对肠道相关残留病毒的免疫反应淋巴组织，以及 3) 使用新型 SIV 保守元件 (CE) DNA 疫苗来集中 T 细胞对高度保守的病毒序列的反应，这些序列如果发生突变，将带来更大的适应成本。我们的总体假设是，疫苗诱导的功能性治愈是由强烈的粘膜 CD8 反应介导的，并且将这些反应集中在肠道上，最大限度地抑制感染和针对更保守的表位，从而抑制更广泛的可能的病毒变异并选择更适合的病毒。 - 计算逃逸突变的成本，将在停止 cART 后最大程度地禁用残留病毒从潜伏病毒库中出现的能力。在操作上，使用优化的 cART 和粘膜靶向，我们将比较传统的全抗原和 CE DNA 疫苗，以提高针对保守病毒序列的粘膜和全身 CD8 反应的频率和强度，以及它们对病毒进化和适应性的影响，并确定这些因素在功能性治疗中的作用。我们的具体目标是：1) 确定表达完整抗原的 LT 佐剂传统 SIV DNA 疫苗与更有效的 cART 一起使用时的治疗效果。 2) 确定SIV CE免疫原是否会提高治疗效果。 3) 定义功能性治疗背后的免疫和病毒学机制。通过拟议的研究，我们将定义疫苗诱导功能性治愈的病毒学和免疫特征，并确定新型 CE DNA 疫苗诱导 SIV 感染功能性治愈的可行性。