Single Amino Acid Differences Are Sufficient for CD4+ T-Cell Recognition of a Heterologous Virus by Cattle Persistently Infected with Bovine Viral Diarrhea Virus

Abstract Cattle that are persistently infected (PI) with one strain of bovine viral diarrhea virus (BVDV) can resolve infection with a second, antigenically heterologous strain but not the homologous strain. Since CD4 + T cells are thought to be critical for the resolution of acute BVDV infection (Howard et al., 1992, Vet. Immunol. Immunopathol. 32, 303–314), we have examined the recognition of a heterologous virus (NADL) by CD4 + T cells from Pe515-PI animals. The immune response of non-PI control cattle challenged with NADL or Pe515ncp was strain cross-reactive, whereas Pe515-PI animals responded to NADL only. The immune repertoire of both groups included NS3, which differs by approximately 1% (9/683) amino acids between these two viruses. Lymphoproliferative responses to proteins and synthetic peptides corresponding to three nonconservative differences in NS3 demonstrated that CD4 + T cells from non-PI control animals responded well to proteins but poorly to the peptides from both viruses. In contrast, PI animals were responsive to heterologous proteins and peptides but nonresponsive to the homologous equivalents. A single amino acid difference between the two sequences was sufficient to allow responsiveness.