Abstract Chronic norovirus infection can cause chronic diarrhea and wasting in immunocompromised patients, including those undergoing hematopoietic stem cell transplantation and with primary immunodeficiency disorders. There are currently no available therapies to treat norovirus. Our preliminary data demonstrates that healthy individuals have T cell immunity against norovirus, and that identified viral epitopes in antigens NS6 and VP1 are well conserved across viral genotypes. The overarching goal of this proposal is the development of a novel treatment for chronic norovirus infection in patients undergoing HSCT. In our previous study, we demonstrated safety and potential efficacy of virus-specific T cells targeting CMV, EBV, and adenovirus as well as the feasibility of this approach. Knowledge of T-cell response to norovirus could enable future trials of adoptive immunotherapy with NSTs, which represents a novel antiviral therapy that could provide long-term protection against norovirus. To classify the T-cell response against norovirus we now propose to take blood from the healthy donors and expand and enrich the norovirus-specific T cells (NSTs) present in donors' blood, followed by extensive characterization of the function of NSTs. We hypothesize that the infusion of NSTs will be safe and effective against norovirus infections in patients post HSCT, and will restore lasting immunity against norovirus. We further hypothesize that norovirus epitopes will correlate with expansion of T cells recognizing immunodominant viral epitopes, which will correspond to stable regions of the viral genome. Through this study, we will address the following specific aims: 1) To determine whether norovirus specific T cells recognize a broad number of MHC Class I and class II restricted epitopes, and 2) To evaluate whether norovirus epitope specific T cells are cross-reactive with a broad panel of isolates encompassing multiple viral strains. Collectively, these aims will identify the range and stability of norovirus epitopes. Completion of this study could provide a novel antiviral therapy which could reduce virus-associated morbidity in HSCT, and will guide future cellular therapy and vaccine trials targeting enteric viruses.