Program Project #1 will use the EBV model of persistent viral infection te characterize the lineage relationship between effector and memory responses and the factors that influence the evolution ef antigen- specific CDS+ T cell responses into the memory CD8+ T cell repertoire. Work outlined in this project addresses the collective hypotheses that virus-specific CD8+ T cell repertoires change quantitatively and qualitatively over time following acute infection, and that differences in virus-specific CDS+ T cell repertoires may influence the control of viral replication, viral sequence evolution, and disease pathogenesis. Changes in the EBV-specific CD8+ T cell repertoire over time may be based en inherent properties of EBV-specific CDS+ T cell clones (specificity, TCR usage, avidity, genome-wide transcriptional profiles), prior infections and ongoing antigenic exposure.
Specific Aim 1 will use'TCR CDR3a and p sequencing te define the relationship between the EBV epitope-specific TCR repertoires at serial time points from the acute through the memory phases ef the T cell response.
Specific Aim 2 will define genome-wide expression profiles in EBV epitope-specific CD8+ T cells during the acute phase of the T cell response and CDS+ T cell persistence into the memory pool in order te examine whether specific gene expression signatures correlate with the size ofthe EBV epitope-specific CD8+ T cell response during AIM, persistence er non-persistence of the EBV epitope-specific CD8+ T cell response, control ef EBV replication, and/or AIM symptoms in primary infection.
Specific Aim 3 will use novel deep sequencing methods to define EBV founder populations and track EBV sequence evolution in oropharyngeal secretions and peripheral bleed B cells ever time following infection. Characterization of intra-host EBV genetic sequence variability should improve our understanding ef anatomical sites ef EBV replication and persistence and should better define factors (viral replication, repeated infections, immune selective pressures) that contribute te EBV sequence diversity over time. Project 1 integrates experimentally and conceptually with the proposed characterization of cress-reactive CDS+ T cells in Project 2 (Selin) and will use the services ef all 3 Cores.
The proposed studies along with those in Project 2, will provide insight inte 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 may contribute to either viral control or disease. Ultimately, we hope that they will help to inform the development ef antiviral vaccines that afford long-term protection against infection or disease, while minimizing the potential adverse effects of these vaccines.
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|Clute, Shalyn C; Naumov, Yuri N; Watkin, Levi B et al. (2010) Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes. J Immunol 185:6753-64|
|Cornberg, Markus; Clute, Shalyn C; Watkin, Levi B et al. (2010) CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections. J Immunol 184:2825-38|
|Co, Mary Dawn T; Kilpatrick, Elizabeth D; Rothman, Alan L (2009) Dynamics of the CD8 T-cell response following yellow fever virus 17D immunization. Immunology 128:e718-27|
|Hadinoto, Vey; Shapiro, Michael; Greenough, Thomas C et al. (2008) On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 111:1420-7|
|Souza, Tatyana A; Stollar, B David; Sullivan, John L et al. (2007) Influence of EBV on the peripheral blood memory B cell compartment. J Immunol 179:3153-60|
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