Virus like particles as a therapeutic vaccine for HIV

病毒样颗粒作为艾滋病毒治疗疫苗

• 批准号: 9326364
• 负责人: SARAH BECK
• 金额: $ 13.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-04 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326364
• 关键词: AIDS prevention; AIDS/HIV problem; Acute; Advisory Committees; American; Animal Model; Antigens; Award; Blood; Bovine Papillomavirus; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Capsid; Cardiac; Cells; Cellular Immunity; Chronic; Clinical; Clinical Research; Community Outreach; Comparative Pathology; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Development; Doctor of Philosophy; Educational workshop; Environment; Epitopes; Exhibits; Funding; Future; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Human; Immune response; Immune system; Immunologics; Immunology; Individual; Infection; Knowledge; Laboratory Research; Life; Macaca; Macaca mulatta; Measures; Mediating; Memory; Mentors; Mentorship; Mind; Modeling; Monkeys; Mus; Mutation; Nerve Degeneration; Outcome; Pathologist; Patients; Plasma; Play; Primary Infection; Proteins; Research; Research Personnel; Resources; Rest; Role; SIV; Scientist; Shock; T-Lymphocyte; Testing; Time; Tissues; Training; Translational Research; Universities; Vaccinated; Vaccination; Vaccines; Veterinarians; Viral; Viral Load result; Viral Vaccines; Viral reservoir; Virus; Virus Diseases; Virus Replication; Virus-like particle; Work; adaptive immunity; antiretroviral therapy; arm; base; career; career development; collaborative environment; college; design; experience; gag Gene Products; humanized mouse; innovation; killings; medical schools; meetings; mouse model; multidisciplinary; nonhuman primate; novel virus; pandemic disease; prevent; programs; public health relevance; reactivation from latency; response; simian human immunodeficiency virus; skills; therapeutic vaccine; tool; vaccination strategy; viral rebound

Abstract Candidate: The objective of this K01 SERCA application is to provide the mentorship, support, and protected time necessary for Dr. Sarah Beck, DVM, PhD, DACVP to progress into a successful and productive career in independent translational research in the field of vaccine immunology. Dr. Beck is a veterinarian with extensive experience in viral immunology and nonhuman primate models of simian immunodeficiency virus (SIV). Her training at Johns Hopkins has provided her with expertise in a wide variety of animal models and comparative pathology, and she also is a Diplomate in the American College of Veterinary Pathologists (ACVP), making her a uniquely qualified candidate for translational research. Under the mentorship of a well-rounded and experienced scientific advisory committee and her co-mentors, Dr. Joel Blankson and Dr. Joseph Mankowski, the proposed training will allow her to expand her expertise into the field of vaccine immunology and the use of humanized mouse models of viral immunopathogenesis. Research Plan: Despite the fact that combined antiretroviral therapy is able to control viral replication and prolong the life of HIV infected individuals, HIV remains a pandemic without a cure. One of the largest blockades to achieving HIV cure is proving to be the presence of virus in resting CD4+ T cell reservoirs. Myriad studies have identified cell-mediated immunity (CMI) as an important mechanism for controlling viral replication. Although effective combined antiretroviral therapy (cART) prevents new rounds of HIV infection, it is incapable of eliminating pre-existing infected CD4+ cells, which are the most likely precursors to the majority of latently infected cells. In contrast, CD8+ T cells are capable of eliminating either productively infected or non-productively infected cells. This approach is supported by recent data using a CMV-based HIV vaccine, which showed that the presence of vaccine-induced CD8+ T cells in primary infection in SIV-infected rhesus were able to eliminate the viral reservoir entirely. The development of broad, persistent HIV Gag-specific CTL responses is believed to play a major role in control of viral replication and determination of clinical outcome. With this in mind, Dr. Beck plans to induce a robust, broad, HIV Gag-specific CD8+ T cell response using a novel virus like protein (VLP) platform with the goal of reducing or eliminating the viral reservoir by inducing effective CTL-mediated control of viral replication in primary HIV infection. This VLP vaccination strategy has several advantages over other vaccine strategies: 1) this VLP is a subunit type vaccine constructed on a bovine papillomavirus capsid, which is a foreign antigen to mice, monkeys, or humans, and therefore can be used across species easily, 2) it preferentially stimulates CTL response over humoral responses, and 3) it is able to induce a strong effector memory response. The overarching hypothesis of the proposed studies is that vaccination for HIV using the novel virus like protein (VLP) platform will stimulate broad HIV Gag-specific cytotoxic T cells, resulting in effective T cell-mediated killing of HIV-infected cells in primary infection, reducing the viral reservoir in HIV-infected BLT mice. She will test this hypothesis with the following specific aims: Specific Aim #1: Determine if VLPs can elicit broadly reactive HIV Gag-specific CTLs capable of controlling acute HIV replication in newly infected BLT mice Specific Aim #2: Determine if VLP elicited CTLs can prevent the accumulation of HIV escape mutations in newly infected BLT mice and decrease CD4+ T cell infection Specific Aim #3: Determine if VLP elicited CTLs can reduce the viral reservoir in HIV-infected mice on combination antiretroviral therapy (cART). This SERCA funding will allow Dr. Beck to receive the mentorship and skills needed to succeed as a independent scientist, and these studies will pave the way towards her future R01 funding to test VLP vaccination in larger macaque studies. Environment: The carefully crafted research plan developed by the applicant and her scientific mentor Joel Blankson is designed to give her interactive and multidisciplinary training in the highly collaborative environment at Johns Hopkins University. The Johns Hopkins University School of Medicine is a world- renowned leader in HIV research, encompassing programs in clinical and laboratory research, community outreach and HIV prevention, with the top experts in the field, providing the fertile ground for innovation and state of the art HIV research. This award will also allow Dr. Beck to attend yearly scientific meetings where she can further broaden her knowledge in viral and vaccine immunology, attend workshops, and network to gain recognition in the field. Her strong mentoring team, institutional support, and resource-rich environment will provide Dr. Beck with the scientific and career development needed to prepare her for a future as an independent researcher in an academic setting.

抽象的 候选人：此K01 SERCA应用的目的是提供指导，支持和保护 Sarah Beck博士，DVM，博士，DACVP的必要时间才能晋升为成功而富有成效的职业 疫苗免疫学领域的独立翻译研究。贝克博士是一位兽医 在病毒免疫学和非人类灵长类动物模型（SIV）方面的经验。她 约翰·霍普金斯（Johns Hopkins）的培训为她提供了各种动物模型和比较的专业知识 病理学，她也是美国兽医病理学家学院（ACVP）的外交官，使她成为 转化研究的独特资格候选人。在全面的指导下 经验丰富的科学咨询委员会和她的联合委员 拟议的培训将使她能够将自己的专业知识扩展到疫苗免疫学领域，并使用 人源化的病毒免疫发病的小鼠模型。 研究计划：尽管抗逆转录病毒疗法合并能够控制病毒复制和 延长艾滋病毒感染个体的寿命，艾滋病毒仍然是一场大流行，无法治愈。最大的 实现HIV治疗的阻塞被证明是静止的CD4+ T细胞储层中的病毒。无数 研究已将细胞介导的免疫（CMI）确定为控制病毒的重要机制 复制。尽管有效联合抗逆转录病毒疗法（CART）阻止了新的HIV感染，但 无法消除已有感染的CD4+细胞，这是多数的最可能的前体 潜在感染的细胞。相反，CD8+ T细胞能够消除有效感染或 非生产感染的细胞。使用基于CMV的HIV疫苗的最新数据支持了这种方法， 这表明在SIV感染的恒河猴中，疫苗诱导的CD8+ T细胞的存在 能够完全消除病毒库。广泛的，持续的HIV特异性CTL的发展 据信反应在控制病毒复制和确定临床结果中起着重要作用。 考虑到这一点，贝克博士计划使用A诱导强大的，广泛的HIV特异性CD8+ T细胞响应 新型病毒（如蛋白质（VLP）平台），目的是通过诱导减少或消除病毒储存 在原发性HIV感染中，有效的CTL介导的病毒复制控制。这种VLP疫苗接种策略具有 比其他疫苗策略的几个优点：1）该VLP是在A上构建的亚基类型疫苗 牛乳头瘤病毒capsid是对小鼠，猴子或人类的外国抗原，因此可以是 2）它优先刺激CTL反应而不是体液反应，而3） 能够诱导强大的效应子记忆响应。拟议研究的总体假设是 使用新型病毒（如蛋白质（VLP）平台）为HIV疫苗接种将刺激广泛的HIV gag特异性 细胞毒性T细胞，导致在原发性感染中有效T细胞介导的HIV感染细胞杀死，从而减少 HIV感染的BLT小鼠中的病毒储存剂。她将以以下特定目的检验这一假设： 特定目的＃1：确定VLP是否可以引起能够控制的广泛反应性HIV特异性CTL 新感染的BLT小鼠的急性HIV复制 特定目的＃2：确定VLP是否引起CTL是否可以防止HIV逃脱突变的积累 新感染的BLT小鼠并减少CD4+ T细胞感染 特定目的＃3：确定VLP是否引起CTL是否可以减少HIV感染的小鼠的病毒储量 组合抗逆转录病毒疗法（CART）。 这项SERCA资金将使贝克博士能够获得成功的指导和技能 独立科学家，这些研究将为她未来的R01资金铺平道路，以测试VLP 在较大的猕猴研究中疫苗接种。 环境：申请人及其科学导师乔尔制定的精心制作的研究计划 布兰克森旨在在高度协作中进行互动和多学科培训 约翰·霍普金斯大学的环境。约翰·霍普金斯大学医学院是一个世界 - 艾滋病毒研究的知名领导者，涵盖临床和实验室研究的计划，社区 外展和艾滋病毒的预防，该领域的高级专家为创新和 艾滋病毒研究状态。该奖项还将允许贝克博士参加她的年度科学会议 可以进一步扩大她在病毒和疫苗免疫学，参加研讨会和网络以获得的知识 在现场的认可。她强大的指导团队，机构支持和资源丰富的环境将 向贝克博士提供科学和职业发展，为她做好准备，为她做好准备 在学术环境中的独立研究人员。