Vaccine induced T-cell protection against SIV infection

描述（由申请人提供）：该候选人致力于将基础研究和患者护理相结合的职业，特别关注艾滋病毒疾病、发病机制和疫苗开发领域的转化科学。他是医学博士博士毕业于德国的基尔大学，并在麻省理工学院和哈佛的Ragon研究所（以前称为伙伴艾滋病研究中心）进行了关于自然HIV感染中保护性CD 4+和CD 8 + T细胞相关性的博士后研究。他目前是马萨诸塞州总医院/布里格姆妇女医院传染病临床和研究员，哈佛医学院医学讲师。候选人以前的道路帮助他定义和提高他的科学生涯，将他的研究兴趣从纯粹的HIV发病机制转移到转化方面，特别是疫苗导向的问题。他特别感兴趣的是研究疫苗引发的T细胞反应与保护相关的相关性，并希望应用一些新的纳米技术;他在博士后研究期间开发了这些技术，以进一步剖析抗病毒T细胞的特征。候选人以前的工作非常富有成效，使他能够在人类T细胞免疫学方面获得强大的知识基础，并在免疫学研究技术方面获得扎实的技能。K 08机制下的指导培训将使他能够将以前获得的免疫学技能转化为足够的科学专业知识、出版物和合作， 艾滋病毒疫苗学领域，并将允许他继续发展为一名医生科学家。候选人的长期目标是在学术界建立自己作为一个独立资助的研究人员从事以病人为导向的艾滋病毒疫苗开发研究。他很幸运有两位导师，Dan Barouch博士和布鲁斯步行者博士，他们在疫苗开发和细胞免疫学领域拥有丰富的经验，之前都曾成功指导过K奖获得者。此外，候选人将被安置在Ragon研究所，该研究所提供了一流的研究基础设施，丰富的科学社区，非常适合候选人成功开展其项目。此外，一个由杰出科学家组成的委员会将监督他走向独立的进程。预防性HIV疫苗的开发是极其困难的，尽管在某些情况下在自然HIV感染中诱导中和抗体，但很可能只有T和B细胞应答的组合活性才能预防感染。T细胞很可能不仅是帮助产生有效的B细胞应答所必需的，而且是快速遏制和清除最初局部粘膜感染所必需的，从而防止病毒传播， 如果发生感染，调节病毒血症。最近在恒河猴中的两项研究表明，在诱导T细胞免疫后，可以实现对感染的易感性降低和感染后病毒控制（和潜在的清除）。在这两项研究中，SIV特异性T细胞反应的存在与SIV获得或控制的60-80%减少有关。然而，人们对这些疫苗诱导的保护性T细胞反应的功能特征以及它们是否能够归巢到感染部位知之甚少，在那里它们可以提供最大程度的保护。了解这两种疫苗引起的抗病毒免疫应答的精确功能相关性为开发特异性扩增这种免疫活性的新方法以用于未来的HIV疫苗设计提供了独特的机会。此外，综合比较解剖 在这2种动物模型中诱导的T细胞应答可能有助于定义与感染或感染后保护相关的T细胞应答的特定特性。在本提案中，候选人将研究以下假设：接种疫苗的恒河猴的保护作用是由疫苗诱导的CD 4+和CD 8 + T淋巴细胞应答的特定功能和解剖学亚群介导的，与独特的功能性抗病毒特征相关。将解决以下具体目标：1）确定rAd和CMV-载体诱导的CD 4+和CD 8 + T细胞的抗病毒特征与恒河猴中的保护作用相关; 2）确定恒河猴中粘膜rAd诱导的CD 4+和CD 8 + T细胞的抗病毒特性，并研究导致粘膜T细胞归巢和持久性的机制。这些研究将为特异性细胞免疫反应提供重要见解，如果疫苗诱导的抗体不能提供感染的杀菌保护，这些细胞免疫反应可能为感染/疾病提供额外的关键屏障，并将有助于指导未来有效的疫苗开发。

DESCRIPTION (provided by applicant): The candidate is dedicated to a career that combines basic research and patient care with a particular focus on translational science in the area of HIV disease, pathogenesis and vaccine development. He is an M.D.-Ph.D. graduate from the University of Kiel, Germany and did his postdoctoral research fellowship on correlates of protective CD4+ and CD8+ T cells in natural HIV infection at the Ragon Institute of MGH, MIT and Harvard (formerly known as Partners AIDS Research Center). He is currently a clinical and research fellow in Infectious Disease at Massachusetts General Hospital/Brigham and Women's Hospital and an Instructor in Medicine at Harvard Medical School. The candidate's previous path has helped him to define and sharpen his scientific career moving the focus of his research interest from pure HIV pathogenesis to translational aspects, in particular vaccine directed questions. He is particularly interested in investigating correlates of vaccine-elicited T cell responses associated with protection and would like to apply some of the novel nano-technologies; he had developed during his post-doctoral fellowship, to further dissect antiviral T cell characteristics. The candidate's previous work has been very productive and has enabled him to gain a strong knowledge base in human T cell immunology and a solid skill set in immunological research technologies. Mentored training under the K08 mechanism would allow him to translate his previously acquired immunological skills to develop sufficient scientific expertise, publications and collaborations in the field of HIV vaccinology and would permit his continued development as a physician scientist. The candidate's longer-term goal is to establish himself within academia as an independently funded investigator engaged in patient oriented research on HIV vaccine development. He is fortunate to have two mentors, Drs. Dan Barouch and Bruce Walker, who have extensive experience in the field of vaccine development and cellular immunology and who both have successfully mentored K-awardees before. Furthermore the candidate will be placed at the Ragon Institute, which offers superb research infrastructure, a rich scientific community and is highly suited for the candidate's successful conduction of his project. In addition, a committee of distinguished scientists will oversee his progress toward independence. The development of a prophylactic HIV vaccine has been extremely difficult and although neutralizing antibodies are induced in some instances in natural HIV infection, it is likely that only the combined activity of T and B cell responses can prevent infection. T cells are most likely not only necessary to help the generation of effective B cell responses but also to rapidly contain and clear an initially localized mucosal infection, thereby preventing viral spread, and to modulate viremia should infection occur. Two recent studies in rhesus macaques have shown that both reduced susceptibility to infection and post-infection viral control (and potential clearance) can be achieved following the induction of T cell immunity. In both studies the presence of robust SIV-specific T cell responses was linked to a 60-80% reduction in SIV acquisition or control. Yet little is known about the functional characteristics of these vaccine-induced protective T cell responses and whether they are able to home to the sites of infection, where they may provide the greatest level of protection. Understanding the precise functional correlate of the antiviral immune response(s) elicited by these 2 vaccines offers a unique opportunity to develop new approaches at specifically amplifying such immunological activity for future HIV vaccine design. Moreover, comprehensive comparative dissection of the T cell response induced in these 2 animal models may help define the specific properties of the T cell response associated with protection from or after infection. In this proposal, the candidate will investigate the hypothesis that protection in vaccinated rhesus monkeys is mediated by specific functional and anatomic subsets of vaccine-elicited CD4+ and CD8+ T lymphocyte responses, related to unique functional antiviral profiles. The following specific aims will be addressed: 1) Define the antiviral signature(s) of rAd and CMV-vector induced CD4+ and CD8+ T cells associated with protection in rhesus monkeys; 2) Determine antiviral properties of mucosal rAd-induced CD4+ and CD8+ T cells in rhesus macaques and investigate mechanism(s) leading to mucosal T cell homing and persistence. These studies will provide critical insights into the specific cellular immune responses that may provide an additional key barrier to infection/disease should vaccine-induced antibodies fail to provide sterilizing protection from infection and will help guide future efficacious vaccine development.