HCMV-specific CD8 T cells protect bone marrow transplant patients when used in cellular immunotherapy, and their long-term maintenance is enhanced by CD4 T cells. Importantly, a robust HCMV-specific CD4 T cell response strongly correlates with protection against congenital infection and fewer rejections in kidney transplant patients. In mice, CD4 T cells are absolutely required for controlling persistent MCMV replication in the salivary gland (SG), the main site where the virus replicates for months and is horizontally transmitted, and CD8 T cells provide no control in this organ. We were the first to identify MCMV epitope-specific CD4T cells that arise in several different genetic strains of mice, and are studying the potential of these cells to mediate vaccine protection. We have shown that cosignaling by several key immune pathways (e.g. B7-CD28, PDL1-PD1, OX40-OX40L, 41BB-41BBL) regulates the development and function of MCMV-specific T cells. In turn, viral inhibition of B7-CD28 and CD40-CD40L signaling helps the virus to establish persistent infection and blunt the antiviral CD4 T cell response. We believe that our studies of the mechanism(s) by which the diverse CMV-specific CD4 T cell response is generated will help elucidate how persistent infection is controlled and provide novel insight for vaccine development.