Vaccine induced T-cell protection against SIV infection

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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.