Persistence of virus in whole cells may be a result of immune regulation and stripping of viral antigens off the plasma membranes of infected cells or by virus induced formation of mutants and appropriate genetic selection. In either case the sparsity of viral antigens expressed on the plasma membrane surface allows persistent infected cells to escape immunologic surveillance. Furthermore, potential cytolytic viral infections are regulated to become noncytopathic, viral polypeptides may store in the cytoplasm of specialized cells and the luxury functions of these cells ultimately embarrassed. We have focused our attention on three main model systems which are likely to lead to relevant information on regulation of persistent virus infections and associated cell pathobiology or tissue injury and disease state. These models may well shed light on mechanisms in degenerative and demyelinative diseases of man like multiple sclerosis and amyotrophic lateral sclerosis. Attention has focused on measles virus because we are aware that this virus may remain latent or persistent in man and eventually become activated. Studies look at cell-viral interrelationship, alterations of HLA gene products by virus, and the ability of the humoral and cellular immune system to eliminate virus infected cells. A second model of interest is the formation of defective interfering virus and/or temperature sensitive mutants in regulation of viral persistence and allowing such infected cells to escape immunologic attack. Here our interest focuses both in vitro and in vivo on the role of DIV in acute and persistent LCMV infection as well as the role of ts mutants of mouse hepatitis virus and its wild type in causing primary demyelination and destructions of oligodendrocytes. The third model of interest is a slow virus disease, of which destruction of anterior horn cells is a prominent feature. This is the central nervous system disease caused by WM-1504 virus. Here using a quantifiable and identifiable viral gene product and genetically defined recombinant mice, the controlling factors in resistance and susceptibility can be mapped. Studies on patients with multiple sclerosis have focused on the responses of their peripheral blood lymphocytes against measles virus infected targets. In addition, the presence of thymus derived suppressor cells and the activity of such cells is under investigation.