Herpesviruses induce persistent infections in humans and have significant health implications. For example, Epstein-Barr virus (EBV), which establishes latency in B cells, is associated with infectious mononucleosis (glandular fever) and the development of malignancy. Cytolytic CD8+ T lymphocytes (CTL) are believed to play a major role in controlling the acute and latent stages of infection and are also a major component of the mononucleosis. However, the relationship between CTL responses to the acute and latent phases of infection and the involvement of CD8+ T cells in mononucleosis are poorly understood. MHV-68 is a murine gamma-herpesvirus with significant biological similarity to EBV and structural homology to Herpesvirus samiri and human herpesvirus-8 (associated with Kaposi's sarcoma). This virus provides an important experimental model for dissecting the CD8+ T cell response to persistent herpesvirus infection. Intranasal infection of mice with MHV-68 establishes an acute infection in the lungs, which is cleared within 8 days, and a persistent, latent infection in B cells that lasts for the life of the animal. In addition, about three weeks after infection (after clearance of infectious virus from the lung), the virus causes a pathogenesis similar to the infectious mononucleosis that sometimes is associated with EBV infection of adolescents. The experiments outlined in this proposal will determine the relationship between the CD8+ T cell response to acute and latent MHV-68 infection, and the CD8+ T cells involved in the mononucleosis syndrome.
Aim 1 will determine the genetic influence on the development of the mononucleosis phase of the disease, and will characterize the longevity and function of the activated CD8+ T cells in the peripheral blood.
Aim 2 will identify the antigens recognized by CD8+ T cells in the peripheral blood during the mononucleosis phase of the infection. In particular, these studies will determine whether the predominance of activated Vb4+CD8+ T cells in the peripheral blood is driven by a viral peptide antigen or a superantigen. Finally, in Aim 3, the T cell epitopes that drive the CTL response to acute MHV-68 infection will be identified to investigate the establishment of T cell memory to a persistent virus infection. These studies will also determine the relationship between the CD8+ T cells involved in the infectious mononucleosis, and the CD8+ T cell response to primary infection.
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