In recent years, tremendous advances have been made in understanding viral biology and immune responses to viral infection. In the majority of viral infections, the acute phase of infection is associated with successful immune responses leading to the containment of viremia and viral spread. However, certain viruses, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), are able to establish persistent infection. In this proposal, we are going to use the Lymphochoriomeningitis virus (LCMV) model of infection to probe why one set of immune responses is hampered in chronic infection. LCMV has been widely used as a murine model of host pathogenesis, and depending on the LCMV strain utilized, either self-resolving acute infection (e.g., LCMV Armstrong) or persistent infection (e.g., LCMV clone 13) can be obtained. The work we performed in our original SCORE pilot project has thus far lead to the characterization of a set of nine CD4+ T-cell epitopes after LCMV Armstrong infection, showing a broad repertoire of responses in the setting of successful control of viral replication. However, these responses were not detected in chronic infection with LCMV clone 13. Even though these responses could be elicited after immunization, subsequent LCMV clone 13 infection resulted in their suppression. It has also been recently shown by other groups that programmed death-1 (PD-1) is up-regulated in T-cells in chronic infection, resulting in their apoptosis. It remains to be seen whether this applies to CD4+ T-cells in persistent LCMV infection. We hypothesize that infection with persistent LCMV viral strains leads to impairment of LCMV-specific CD4+ T-cell immunity contributing to the establishment of persistent infection. The long-term goal of this proposal is to mechanistically define how CD4+ T-cells are impaired in chronic infection. To address this, our specific aims consist of the following: (1) to determine whether effective LCMV-specific CD4+ T-cell responses develop after persistent LCMV infection using virus-pulsed antigen presenting cells and CD4+ T-cells from infected animals in ELISPOT assays;(2) to understand whether CD4+ T-cell impairment is a result of deletion and/or dysfunction in persistent LCMV infection by following CD4+ T-cells with tetramer staining and lymphokine production;(3) to determine whether CD4+ T-cell responses can be rescued in the setting of LCMV persistent infection by investigating if CD4+ T-cells express high levels of PD-1 which can be blocked.
| Dow, Courtney; Henderson, Ryan; Sette, Alessandro et al. (2013) CD4(+) T-cell inhibitory ligands: a tool for characterizing dysfunctional CD4(+) T cells during chronic infection. Immunology 140:61-9 |
| Dow, Courtney; Oseroff, Carla; Peters, Bjoern et al. (2008) Lymphocytic choriomeningitis virus infection yields overlapping CD4+ and CD8+ T-cell responses. J Virol 82:11734-41 |
