Altered peptide ligands (APLs) and their antagonistic or partial agonistic character–influencing T cell activation have mainly been studied in vitro Some studies have shown APLs as a viral escape mechanism from cytotoxic CD8+ T cell responses in vivo. However, whether infection or superinfection with a virus displaying an antagonistic T cell epitope can alter virus–host relationships via inhibiting T cell–mediated immunopathology is unclear. Here, we evaluated a recently described CD4+ T cell escape lymphocytic choriomeningitis virus (LCMV) variant that in vitro displayed antagonistic characteristics for the major histocompatibility complex class II–restricted mutated epitope. Mice transgenic for the immunodominant LCMV-specific T helper epitope that usually succumb to wild-type LCMV-induced immunopathology, survived if they were simultaneously coinfected with antagonistic variant but not with control virus. The results illustrate that a coinfecting APL-expressing virus can shift an immunopathological virus–host relationships in favor of host survival. This may play a role in poorly cytopathic long-lasting virus carrier states in humans.