Abstract
Humans and animals are infected by multiple endogenous and exogenous viruses but few agents cause overt tissue damage. We review the circumstances which favor overt disease expression. These can include intrinsic virulence of the agent, new agents acquired from heterologous species, the circumstances of infection such as dose and route, current infection with other agents which includes the composition of the microbiome at mucosal and other sites, past history of exposure to other infections as well as the immune status of the host. We also briefly discuss promising therapeutic strategies that can expand immune response patterns that minimize tissue damaging responses to viral infections.