Three monoclonal antibodies (mAbs), 49.8.9, 36.2.2, and 54.2.8, made to the group A streptococcus M5 serotype identify crossreactive epitopes in cardiac tissues and also neutralize a highly myocarditic variant of coxsackievirus B3 (H3). Mutants of H3 were selected with these mAbs and evaluated for pathogenicity compared with the wild-type virus. H3 and the mutant variants selected with mAbs 36.2.2 (H3-36) and 54.2.8 (H3-54) induced severe myocarditis in DBA/2 (H-2d) and A/J (H-2a) male mice, whereas CBA (H-2k) mice were disease resistant. The virus variant isolated with mAb 49.8.9 (H3-49) was strikingly different and caused disease in CBA and A/J mice but not in DBA/2 animals, suggesting that the major histocompatibility complex association of the disease had been altered. This hypothesis was confirmed by using B10 congenic mice. In addition, T lymphocytes from the H3 and H3-49 virus-infected mice responded to distinctly different peptides in the streptococcal M protein, suggesting that certain epitopes of infectious agents which are shared with host tissues may be critical in determining disease susceptibility in genetically distinct individuals.