It is well established that chronic viral infections can cause immune suppression resulting in increased susceptibility to other infectious diseases. However, the effects of chronic viral infection on T-cell responses and vaccination against highly pathogenic viruses is not well understood. We have recently shown that C57BL/6 (B6) mice lose their natural resistance to wild type ectromelia virus (ECTV) when chronically infected with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13). Here we compared the T-cell response to ECTV in mice previously immunologically naïve, that were chronically infected with CL13, or that were convalescent from acute infection with the Armstrong (Arm) strain of LCMV. Our results show that mice chronically infected with CL13 but not those that recovered from Arm have highly defective ECTV-specific CD8+ and CD4+ T-cell responses to WT ECTV. These defects are at least partly due to the chronic infection environment. Yet, mice chronically infected with CL13 survived without signs of disease infection with ECTV-Δ036, a mutant ECTV that is highly attenuated. Strikingly, mice chronically infected with CL13 mounted a strong CD8+ T-cell response to ECTV-Δ036 and survived without signs of disease to a subsequent challenge with ECTV. Our work suggests that enhanced susceptibility to acute viral infections in chronically infected individuals can be partly due to poor T-cell responses, but that sufficient T-cell function can be recovered and resistance to acute infection restored by immunization with highly attenuated vaccines. [ABSTRACT FROM AUTHOR]