Naturally Occurring Frameshift Mutations in the tvb Receptor Gene Are Responsible for Decreased Susceptibility of Chicken to Infection with Avian Leukosis Virus Subgroups B, D, and E

Abstract

The group of highly related avian leukosis viruses (ALVs) in chickens are thought to have evolved from a common retroviral ancestor into six subgroups, A to E and J. These ALV subgroups use diverse cellular proteins encoded by four genetic loci in chickens as receptors to gain entry into host cells. Hosts exposed to ALVs might be under selective pressure to develop resistance to ALV infection. Indeed, resistance alleles have previously been identified in all four receptor loci in chickens. The gene encodes a receptor, which determines the susceptibility of host cells to ALV subgroup B (ALV-B), ALV-D, and ALV-E. Here we describe the identification of two novel alleles of the receptor gene, which possess independent insertions each within exon 4. The insertions resulted in frameshift mutations that reveal a premature stop codon that causes nonsense-mediated decay of the mutant mRNA and the production of truncated Tvb protein. As a result, we observed that the frameshift mutations in the gene significantly lower the binding affinity of the truncated Tvb receptors for the ALV-B, ALV-D, and ALV-E envelope glycoproteins and significantly reduce susceptibility to infection by ALV-B, ALV-D and ALV-E and Taken together, these findings suggest that frameshift mutation can be a molecular mechanism of reducing susceptibility to ALV and enhance our understanding of virus-host coevolution. Avian leukosis virus (ALV) once caused devastating economic loss to the U.S. poultry industry prior the current eradication schemes in place, and it continues to cause severe calamity to the poultry industry in China and Southeast Asia, where deployment of a complete eradication scheme remains a challenge. The gene encodes the cellular receptor necessary for subgroup B, D, and E ALV infection. Two allelic variants that resulted from frameshift mutations have been identified in this study, which have been shown to have significantly reduced functionality in mediating subgroup B, D, and E ALV infection. Unlike the control of herpesvirus-induced diseases by vaccination, the control of avian leukosis in chickens has relied totally on virus eradication measures and host genetic resistance. This finding enriches the allelic pool of the gene and expands the potential for genetic improvement of ALV resistance in varied chicken populations by selection.

Genetic Polymorphism of Avian Leukosis Virus Host Receptors in Korean Native Chickens and Establishment of Resistant Line

“…Indeed, there have been many reports that resistance to ALV subgroups can be naturally acquired by nucleotide mutations in host receptors. Single nucleotide polymorphisms in the genes encoding the TVA and TVB receptors affect viral binding affinity, while insertions or deletions of multiple nucleotides induce frameshift mutations, ultimately affecting viral resistance (Elleder et al, 2004;Reinisova et al, 2008;Reinisova et al, 2012;Chen et al, 2015;Li et al, 2018).…”

“…Single nucleotide substitutions in the tvb gene regions encoding cysteine-rich domain (CDR) 1 (tvb r1 ) or CDR3 (tvb r3 ) induce premature stop codons that generate a truncated TVB receptor and decrease susceptibility of chickens to ALV-B, -D, and -E (Chen et al, 2017;Klucking et al, 2002). In addition, a G to C single nucleotide substitution (tvb r2 ) induces a cysteine to serine (C125S) amino acid alteration that lowers virus binding affinity (Reinisova et al, 2008), and insertions of two (tvb r4 ) or one (tvb r5 ) nucleotides in tvb exon 4 induces frameshift mutations, leading to expression of a truncated TVB receptor and reduced susceptibility to ALV-B, -D, and -E infection (Li et al, 2018). TVC is a member of the immunoglobulin superfamily, most similar to mammalian butyrophilins, and introduction of a premature stop codon in the gene encoding TVC confers resistance to ALV-C in chickens (Elleder et al, 2005).…”

Avian Leucosis Virus-Host Interaction: The Involvement of Host Factors in Viral Replication

“…Recently, two Tvb variants designated Tvb R4 and Tvb R5 were identified, which had insert “AG” between amino acid residues 291 and 292, and “A” between amino acid residues 359 and 360, respectively. Both insertions induced the generation of truncated Tvb proteins, causing the partially functional loss of receptors for ALV-B, ALV-D, and ALV-E ( 26 ). Several amino acid residues involving the binding and viral entry were identified in the Tvb.…”

Untitled

“…In recent years significant progress has been made in the study of resistance to transmissible spongiform encephalopathies of Capra hircus [11]. The alleles of resistance to avian leukemia virus was mapped for Gallus gallus domesticus [12]. New achievements in this area are steadily growing.…”