The gamma-herpesviruses, including EBV and KSHV, are persistent, oncogenic human pathogens that are widely disseminated in the population and are associated with human disease ranging from infectious mononucleosis to several malignancies. An important goal is the development of preventative vaccines. We have taken advantage of an experimental model, murine gamma-herpesvirus-68 (MHV-68), to dissect early events in the viral infection, to characterize the cellular and humoral immune response, and to test vaccination strategies. Our earlier vaccination studies have shown that vaccination can reduce the lytic load, but have so far failed to prevent the establishment of latency. However, new preliminary data show that latent infection is established in the lung as early as three days after infection, suggesting that efficient vaccines must quickly target infectious virus and lytically- and latently-infected cells in the lung. Based on these observations and recent advances in the field of T cell memory, we hypothesize that vaccination strategies emphasizing pulmonary immunity to both lytic and latent antigens will generate strong protective immunity. In addition, preliminary data showing that the presence of neutralizing antibody at the time of infection greatly reduced the peak lytic load suggests that neutralizing antibody may augment protective cellular immunity by controlling viral titers during the protective recall T cell response. The goal of the current studies is to characterize epitope expression (Aim 1) and virus-specific T cells (Aim 2) during acute and latent MHV-68 infection.
In Aim 3, we will build on this information and use this well-characterized viral model as a """"""""proof of principal"""""""" test for epitope-based vaccination strategies for the gamma-herpesviruses. ? ? ?
|Hu, Zhuting; Blackman, Marcia A; Kaye, Kenneth M et al. (2015) Functional heterogeneity in the CD4+ T cell response to murine ?-herpesvirus 68. J Immunol 194:2746-56|
|Freeman, Michael L; Burkum, Claire E; Cookenham, Tres et al. (2014) CD4 T cells specific for a latency-associated ?-herpesvirus epitope are polyfunctional and cytotoxic. J Immunol 193:5827-34|
|Freeman, Michael L; Roberts, Alan D; Burkum, Claire E et al. (2014) Promotion of a subdominant CD8 T cell response during murine gammaherpesvirus 68 infection in the absence of CD4 T cell help. J Virol 88:7862-9|
|Freeman, Michael L; Burkum, Claire E; Lanzer, Kathleen G et al. (2013) Gammaherpesvirus latency induces antibody-associated thrombocytopenia in mice. J Autoimmun 42:71-9|
|Casiraghi, Costanza; Shanina, Iryna; Cho, Sehyun et al. (2012) Gammaherpesvirus latency accentuates EAE pathogenesis: relevance to Epstein-Barr virus and multiple sclerosis. PLoS Pathog 8:e1002715|
|Freeman, Michael L; Burkum, Claire E; Woodland, David L et al. (2012) Importance of antibody in virus infection and vaccine-mediated protection by a latency-deficient recombinant murine ýý-herpesvirus-68. J Immunol 188:1049-56|
|Freeman, Michael L; Burkum, Claire E; Jensen, Meghan K et al. (2012) ?-Herpesvirus reactivation differentially stimulates epitope-specific CD8 T cell responses. J Immunol 188:3812-9|
|Freeman, Michael L; Burkum, Claire E; Yager, Eric J et al. (2011) De novo infection of B cells during murine gammaherpesvirus 68 latency. J Virol 85:10920-5|
|Freeman, Michael L; Burkum, Claire E; Lanzer, Kathleen G et al. (2011) Cutting edge: activation of virus-specific CD4 T cells throughout ?-herpesvirus latency. J Immunol 187:6180-4|
|Jia, Qingmei; Freeman, Michael L; Yager, Eric J et al. (2010) Induction of protective immunity against murine gammaherpesvirus 68 infection in the absence of viral latency. J Virol 84:2453-65|
Showing the most recent 10 out of 39 publications