Emerging zoonotic viruses are maintained in the environment by persistently infecting their reservoir hosts without causing disease. Spillover of zoonotic viruses, including hantaviruses, to humans often results in significant morbidity and mortality, such as hantavirus cardiopulmonary syndrome (HCPS) or hemorrhagic fever with renal syndrome (HFRS), which is mediated by excessive proinflammatory and CD8+ T cell responses. The mechanisms mediating the persistence of zoonotic viruses in their reservoir hosts remain largely unknown. Using Seoul virus (SEOV), the species-specific hantavirus that infects Norway rats, as a model, the research presented in this dissertation identifies potential mechanisms of viral persistence and prevention of disease. Unlike in humans, in male rats, proinflammatory responses were reduced or remained unaltered in the lungs, a primary site of viral replication and persistence, during SEOV infection. Regulatory responses, however, were elevated in the lungs of male, but not female, rats and contributed to SEOV persistence and suppression of proinflammatory cytokines in males. Whether, in contrast to rodents, regulatory T cell activity is suppressed in patients with acute HRFS or HCPS to contribute to disease has been suggested, but remains unknown. Glucocorticoids also suppress potentially fatal proinflammatory and cellular responses and have been administered to patients with HFRS and HCPS, but whether suppression of these responses may contribute to viral persistence was not known. Concentrations of corticosterone, the primary glucocorticoid in rodents, were reduced in male, but not female, rats during SEOV infection and low concentrations of corticosterone were associated with elevated amounts of SEOV RNA in the lungs of males. Although males with low corticosterone had elevated regulatory T cell responses, the effects of corticosterone on immune mediators could not explain the pattern of SEOV load in the lungs. Males with low corticosterone, however, had elevated expression of the glycogenase, Mmp9, which could contribute to increased viral dissemination in the lungs by physically disrupting cellular matrices. Understanding the mechanisms mediating how hantaviruses persist in reservoir hosts without causing disease may assist with development of treatments and the prevention of disease in humans. Additionally, maintenance of zoonotic viruses, including hantaviruses, in the environment increases the risk of exposure and transmission to humans, so understanding how these viruses persistently infect their reservoir hosts is critical.