The overall goal of the Program Project structure is to provide an environment that fosters detailed, multi- disciplinary characterization of the development of virus-specific and cross-reactive (XR) CDS+ T cells, using the Epstein Barr virus (EBV) model of human infection. Each project in this Program Project is interdependent with regard to expertise, resources, and experimental design and requires access to high- quality clinical specimens and similar technologies. Core A will provide the necessary scientific leadership (including Internal and External Advisory Boards) and administrative and fiscal support to facilitate these multi-disciplinary, collaborative studies. These multidisciplinary studies will result in large and diverse data sets;experts in bioinformatics and biostatistics will not only assist in the development of an integrated database but will also help develop and apply appropriate analytical approaches. In the absence of a suitable animal model, human studies are essential. The University of Massachusetts Amherst (UMA) Health Services Acute Infectious Mononucleosis (AIM) Clinic provides essential clinical samples and constitutes one of a very few longitudinal AIM cohorts in the world. Over the years, we have altered clinical visit and sample collection schedules to address evolving scientific questions. While the AIM Clinic remains the main source of our clinical samples, the newly created UMA EBV Serosurveillance Cohort will allow us to obtain updated estimates of EBV seropositivity and seroconversion in college students. Work conducted over the past funding period has identified high frequencies of influenza and EBV XR CD8+ T cells in the circulation of a small group of individuals who remain EBV uninfected into their third decade of life and beyond. This has led to a novel hypothesis (i.e., that high frequencies of these cross-reactive CDS+ T cells might protect against EBV infection) and organization of a new cohort (EBV Seronegative;EBV-SN) that will be recruited to address this new hypothesis in the next funding period.
The proposed studies will investigate factors that control the evolution of human antiviral CD8+ T cell responses from the acute effector phase into long-term memory and how antigen-specific or cross-reactive CD8+ T cells contribute to viral control or disease. We hope that they will inform the development of antiviral vaccines that afford long-term protection against infection or disease, while minimizing potential adverse effects. By providing scientific leadership, administrative and fiscal support, an integrated database/data analysis, and unique clinical samples. Core A is essential to the Program Project's overall success.
|Aslan, Nuray; Watkin, Levi B; Gil, Anna et al. (2017) Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires. MBio 8:|
|Song, InYoung; Gil, Anna; Mishra, Rabinarayan et al. (2017) Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope. Nat Struct Mol Biol 24:395-406|
|Watkin, Levi B; Mishra, Rabinarayan; Gil, Anna et al. (2017) Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion. J Allergy Clin Immunol 140:1206-1210|
|Gil, Anna; Yassai, Maryam B; Naumov, Yuri N et al. (2015) Narrowing of human influenza A virus-specific T cell receptor ? and ? repertoires with increasing age. J Virol 89:4102-16|
|Gil, Anna; Kenney, Laurie L; Mishra, Rabinarayan et al. (2015) Vaccination and heterologous immunity: educating the immune system. Trans R Soc Trop Med Hyg 109:62-9|
|Greenough, Thomas C; Straubhaar, Juerg R; Kamga, Larisa et al. (2015) A Gene Expression Signature That Correlates with CD8+ T Cell Expansion in Acute EBV Infection. J Immunol 195:4185-97|
|Renzette, Nicholas; Somasundaran, Mohan; Brewster, Frank et al. (2014) Epstein-Barr virus latent membrane protein 1 genetic variability in peripheral blood B cells and oropharyngeal fluids. J Virol 88:3744-55|
|Chen, Alex T; Cornberg, Markus; Gras, Stephanie et al. (2012) Loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope. PLoS Pathog 8:e1002633|
|Tracy, Sean I; Kakalacheva, Kristina; Lunemann, Jan D et al. (2012) Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol 86:12330-40|
|O'Bryan, Joel M; Potts, James A; Bonkovsky, Herbert L et al. (2011) Extended interferon-alpha therapy accelerates telomere length loss in human peripheral blood T lymphocytes. PLoS One 6:e20922|
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