Vaccine induced T-cell protection against SIV infection

应聘者描述(由申请者提供)：应聘者致力于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翻译科学。他毕业于德国基尔大学医学博士学位，并在麻省理工学院拉贡研究所和哈佛大学(前身为伙伴艾滋病研究中心)完成了自然艾滋病毒感染中保护性CD4+和CD8+T细胞相关性的博士后研究。他目前是麻省总医院/布里格姆妇女医院传染病的临床和研究员，以及哈佛医学院的医学讲师。候选人之前的道路帮助他定义和磨练了他的科学生涯，将他的研究重点从纯粹的艾滋病毒发病机制转移到 翻译方面，特别是针对疫苗的问题。他对研究疫苗引发的T细胞反应与保护相关的相关性特别感兴趣，并希望应用他在博士后期间开发的一些新的纳米技术，以进一步剖析抗病毒T细胞的特征。候选人之前的工作非常有成效，使他在人类T细胞免疫学方面获得了坚实的知识基础，并在免疫学研究技术方面掌握了扎实的技能。K08机制下的指导性培训将使他能够将之前获得的免疫学技能转化为足够的科学专长、出版物和合作 他是艾滋病毒疫苗领域的专家，并将继续发展成为一名内科科学家。这位候选人的长期目标是在学术界确立自己的地位，成为一名独立资助的研究员，从事以患者为导向的艾滋病毒疫苗开发研究。他很幸运有两位导师，丹·巴鲁奇博士和布鲁斯·沃克博士，他们在疫苗开发和细胞免疫学领域拥有丰富的经验，而且都曾成功地指导过K奖获得者。此外，候选人将被安置在拉贡研究所，该研究所提供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地进行他的项目。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。预防性艾滋病毒疫苗的开发是极其困难的，尽管在某些情况下自然感染艾滋病毒会诱导中和抗体，但很可能只有T和B细胞反应的联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细胞反应所必需的，而且也是迅速遏制和清除最初局部的粘膜感染，从而防止病毒传播和 在发生感染时调整病毒血症。最近对恒河猴的两项研究表明，在诱导T细胞免疫后，可以降低感染的易感性和感染后的病毒控制(和潜在的清除)。在这两项研究中，强健的SIV特异性T细胞反应与SIV获取或控制的60%-80%的减少有关。然而，关于疫苗诱导的保护性T细胞反应的功能特征，以及它们是否能够定位于感染部位，在那里它们可能提供最大程度的保护，人们知之甚少。了解这两种疫苗诱导的抗病毒免疫反应(S)的精确功能相关性，为未来的艾滋病毒疫苗设计提供了一个独特的机会，为开发专门放大这种免疫活性的新方法提供了独特的机会。此外，全面的比较解剖， 在这两个动物模型中诱导的T细胞反应的研究可能有助于确定与感染保护或感染后相关的T细胞反应的特定属性。在这项提案中，候选人将研究一种假说，即疫苗对恒河猴的保护是由疫苗诱导的CD4+和CD8+T淋巴细胞反应的特定功能和解剖亚群介导的，与独特的功能抗病毒谱相关。将解决以下具体目标：1)确定Rad和巨细胞病毒载体诱导的与恒河猴粘膜保护相关的CD_4~+和CD_8~+T细胞的抗病毒信号(S)；2)确定恒河猴粘膜Rad诱导的CD_4~+和CD_8~+T细胞的抗病毒特性，并探讨导致粘膜T细胞归巢和持续存在的机制(S)。这些研究将为特定的细胞免疫反应提供关键的见解，如果疫苗诱导的抗体未能提供针对感染的灭菌保护，这些免疫反应可能会为感染/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.