Resistance to Infection by Subgroups B, D, and E Avian Sarcoma and Leukosis Viruses Is Explained by a Premature Stop Codon within a Resistance Allele of the tvb Receptor Gene

Functionally distinct alleles of the autosomal tva, tvb, and tvc loci that encode avian sarcoma and leukosis virus (ASLV) receptors have been defined for chickens (reviewed in references 12 and 22). Two classes of tva and tvc alleles are associated with either susceptibility (tvas and tvcs) or resistance (tvar and tvcr) to infection by subgroup A ASLV or subgroup C ASLV, respectively. The tvb locus is more complex since two chicken alleles of tvb that encode distinct ASLV receptors have been defined: tvbs1 for viral subgroups B, D, and E and tvbs3 for subgroups B and D (1, 2, 9, 20). In addition, there is another type of allele (tvbr) that cannot support entry by any of these ASLV subgroups (12). For each ASLV receptor gene, alleles that confer susceptibility to viral infection are dominant over those associated with resistance. Therefore, the only lines of chickens that are resistant to infection by subgroups A through D ASLVs are those that are homozygous for the resistance alleles of the cognate receptor gene. Resistance to subgroup E viral infection is more complicated because of the existence of endogenous ASLV elements in the chicken germ line which encode subgroup E ASLV-specific envelope (Env) proteins that interfere with the function of the TVBS1 receptor (1, 7). The recessive nature of the tvar, tvbr, and tvcr alleles rules out the possibility that their products interfere, in a dominant-negative manner, with those encoded by the corresponding susceptibility alleles. Instead, the defect(s) associated with these resistance alleles may be due either to their lack of expression or to the existence of specific amino acid substitutions in the corresponding proteins that abolish viral receptor function. The tvas allele encodes a low-density lipoprotein (LDL) receptor-related protein that is a cellular receptor for ASLV subgroup A (5, 6, 26). The TVA protein contains an approximately 40-amino-acid long LDL-A module that harbors the major viral interaction determinants (16, 17, 27, 28). The molecular defect that is associated with the tvar allele has not yet been defined, but a preliminary characterization of this allele has documented no obviously debilitating defects within the LDL-A domain (5). TVB is a tumor necrosis factor receptor (TNFR)-related death receptor that is most similar to the mammalian TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 (1). TVB contains three extracellular cysteine-rich domains and a cytoplasmic death domain which can activate apoptosis (8, 9). Several ASLV subgroups that utilize TVB exhibit an acute cytopathic effect. The death-promoting activity of TVB may contribute to the cell death that is observed in cultures that have been infected by subgroups B and D of ASLV (8, 9, 23, 24). In order to understand the molecular basis for the resistance to viral infection that is associated with the tvbr allele, we have characterized the nature of the defect. This analysis has revealed that the tvbr mRNA harbors a premature stop codon that is predicted to lead to the production of a severely truncated protein.