Optimizing CD8+ T Cell Vaccine Responses Against HIV

优化 CD8 T 细胞疫苗对 HIV 的反应

• 批准号: 8492547
• 负责人: TODD M ALLEN
• 金额: $ 40.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-07 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492547
• 关键词: AIDS/HIV problem; Address; Adenoviruses; Adjuvant; Alleles; Animal Model; B-Lymphocytes; Biological Models; Bone Marrow; CD8B1 gene; Cells; Cellular Immunity; Controlled Study; Cytomegalovirus; DNA; Data; Development; Dose; Epitopes; Evolution; Frequencies; Gagging; Genetic; Genomics; HIV; HIV Antigens; HIV Infections; HIV vaccine; Heterogeneity; Homing; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunologics; Infection; Instruction; Kinetics; Lipids; Liver; Macaca; Macaca mulatta; Mediating; Membrane; Memory; Micelles; Modeling; Mus; Mutation; Pathway interactions; Regimen; SIV; Site; Specificity; System; T cell response; T-Lymphocyte; Testing; Thymus Gland; Time; Translating; Translational Research; Ursidae Family; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; Variant; Viral; Viremia; Virus; Work; base; cost; fitness; immunogenicity; impaired capacity; improved; lymph nodes; mouse model; nanocapsule; nanoparticle; novel; prevent; programs; protective effect; response; vaccine development; vaccine efficacy; vector

Project 1 seeks to apply a rational approach to the optimization of an effective CD8+ T cell response to HIV, capitalizing on viral fitness constraints to exploit the natural limits of HIV sequence evolution and CD8 immunodominance hierarchies and the plasticity of the immune response to block viral escape pathways. It also brings to bear recent advances in high throughput genomic sequencing to tackle the enormous sequence diversity of HIV, while applying novel and potent nanoparticle-based vaccine adjuvant systems. Most importantly, it serves to translate identified correlates of immune control of HIV into a novel humanized mouse model capable of recapitulating HIV infection as well as human HIV-specific immune responses. Thus, this work will enable for the first time the direct study of human (not rhesus monkey) immune responses against HIV (not SIV) in order to define the mechanisms of this protection and interatively improve vaccine approaches to optimize these effects. Project 1 responds to five specific objectives of the HIVRAD Program: 1) Identifying correlates of vaccineinduced immune protection to HIV/AIDS; 2) How vaccine design can better address the heterogeneity of HIV; 3) Improved animal model systems (and challenge viruses) to address vaccine efficacy; 4) Approaches to increase the immunogenicity of HIV antigens (e.g., novel adjuvants), and 5) Determining how immune cells can be mobilized to the portal of infection, and will address the following specific aims: Aim 1: Characterize the magnitude, kinetics, specificity and efficacy of HIV-specific CD8+ T cell responses in the humanized BLT mouse model to facilitate studies of HIV-specific vaccine immunity. Aim 2: Determine whether vaccination can overcome natural CD8+ T cell immunodominance hierarchies to avoid targeting of 'decoy' CD8 epitopes, and induce variant-specific CD8+ T cell responses. Aim 3: Determine whether the induction of strong, mucosal-homing CD8+ T cell responses by novel nanoparticle delivery systems can prevent the early systemic dissemination of HIV in BLT mice.

项目1寻求应用合理的方法来优化有效的CD 8 + T细胞对HIV的反应， 利用病毒适应性约束，利用HIV序列进化和CD 8的自然限制， 免疫优势等级和免疫应答的可塑性阻断病毒逃逸途径。它 也带来了承担高通量基因组测序的最新进展，以解决巨大的 HIV的序列多样性，同时应用新的和有效的基于纳米颗粒的疫苗佐剂系统。 最重要的是，它可以将已鉴定的HIV免疫控制相关物转化为新的人源化抗体。 能够重现HIV感染以及人类HIV特异性免疫应答的小鼠模型。 因此，这项工作将首次使人类（而不是恒河猴）免疫的直接研究成为可能。 针对艾滋病毒（不是SIV）的反应，以确定这种保护的机制， 疫苗方法来优化这些效果。 项目1响应艾滋病毒防治方案的五个具体目标：1）确定疫苗诱导的 艾滋病毒/艾滋病的免疫保护; 2）疫苗设计如何更好地解决 艾滋病毒; 3）改进动物模型系统（和挑战病毒），以解决疫苗效力问题; 4）方法 为了增加HIV抗原的免疫原性（例如，新佐剂），和5）确定免疫 细胞可以被动员到感染的门户，并将解决以下具体目标： 目的1：表征HIV特异性CD 8 + T细胞应答的幅度、动力学、特异性和功效， 人源化BLT小鼠模型，以促进HIV特异性疫苗免疫的研究。 目的2：确定疫苗接种是否可以克服天然CD 8 + T细胞免疫优势等级， 避免靶向“诱饵”CD 8表位，并诱导变体特异性CD 8 + T细胞应答。 目的3：确定新的免疫调节剂是否诱导强的粘膜归巢CD 8 + T细胞应答。 纳米颗粒递送系统可以防止HIV在BLT小鼠中的早期全身传播。