Intronic Deletions That Disrupt mRNA Splicing of the tva Receptor Gene Result in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroup A

Abstract

The group of closely related avian sarcoma and leukosis viruses (ASLVs) evolved from a common ancestor into multiple subgroups, A to J, with differential host range among galliform species and chicken lines. These subgroups differ in variable parts of their envelope glycoproteins, the major determinants of virus interaction with specific receptor molecules. Three genetic loci, tva, tvb, and tvc, code for single membrane-spanning receptors from diverse protein families that confer susceptibility to the ASLV subgroups. The host range expansion of the ancestral virus might have been driven by gradual evolution of resistance in host cells, and the resistance alleles in all three receptor loci have been identified. Here, we characterized two alleles of the tva receptor gene with similar intronic deletions comprising the deduced branch-point signal within the first intron and leading to inefficient splicing of tva mRNA. As a result, we observed decreased susceptibility to subgroup A ASLV in vitro and in vivo. These alleles were independently found in a close-bred line of domestic chicken and Indian red jungle fowl (Gallus gallus murghi), suggesting that their prevalence might be much wider in outbred chicken breeds. We identified defective splicing to be a mechanism of resistance to ASLV and conclude that such a type of mutation could play an important role in virus-host coevolution. Retroviruses enter the host cell through specific receptors, cell surface proteins with high affinity to viral envelope glycoproteins. The interaction between receptors and viral glycoproteins is very complex and includes the initial attachment of the virion, profound conformational changes in the structure of the viral glycoprotein, exposure of fusion peptides, and, ultimately, the fusion of viral and cellular membranes (5, 47). Despite the strict structural requirements for these interactions, hypervariability of retroviral glycoproteins can change the receptor usage and broaden the host range. Indeed, closely related families of retroviruses have evolved into multiple subgroups that utilize different cellular surface proteins as receptors. For example, the group of avian alpharetroviruses avian sarcoma and leukosis viruses (ASLVs) comprise 10 related subgroups, A to J, which either do not interfere at all with each other or interfere only nonreciprocally in infecting chicken cells. The susceptibility of chicken cells to highly related ASLV subgroups A to E is determined by three genetic loci, tva, tvb, and tvc (5, 41). The Tva protein belongs to the family of low-density lipoprotein receptors (LDLRs) (6, 48) and determines susceptibility to the subgroup A ASLVs. The tumor necrosis factor receptor-related protein Tvb confers susceptibility to subgroup B, D, and E ASLVs by three nonoverlapping binding sites (2,3,8), and the Tvc protein, closely related to the mammalian butyrophilins, serves as receptor for C subgroup ASLV (14).The rapid evolution of novel retrovirus envelopes is compelled by the appearance of host entry restrictions. Gen...

Single nucleotide polymorphism variants within tva and tvb receptor genes in Chinese chickens

“…The resistant loci tvar3 and tva?1, whose mutant sites were the same within the first intron of the tva recep tor gene (Reinisova et al, 2012). Therefore, these re sistant loci may be considered as multiple alleles.…”

“…The susceptibility or resistance of chicken cells to subgroup A ALV is determined by the tumor vi rus locus A (tva) locus, which encodes the receptors for ALV-A (Bates et ah, 1993;Gilbert et al, 1994). At present, 4 genetic resistant loci in the tva receptor gene, tva?1, tvar2, tva?3, and tvar4, have been identified in some inbred lines of White Leghorn (Elleder et al, 2004;Reinisova et al, 2012). The tumor virus locus B (in&)locus in chickens determines the susceptibility or resistance of cells to infection by the subgroup B, D, and E ALV (Crittenden et al, 1967).…”

Nonconserved Tryptophan 38 of the Cell Surface Receptor for Subgroup J Avian Leukosis Virus Discriminates Sensitive from Resistant Avian Species

“…Finally, subgroup C ASLVs utilize the Tvc protein of the butyrophilin family with two immunoglobulin-like domains (8). The complete resistance or decreased susceptibility of host chicken cells to a particular ASLV subgroup can then be caused by premature termination or a frameshift in the receptor-encoding loci (8)(9)(10), decreased receptor expression and display (11), and even single amino acid substitutions in the receptor sequence (9,12).…”

Identification of New World Quails Susceptible to Infection with Avian Leukosis Virus Subgroup J

“…However, we cannot exclude the possibility of imperfect correlation between W38 positivity and susceptibility to ALV-J due to another disabling mutation. Actually, the most frequent link between genetic and phenotypic variation is RNA splicing, and splicing defects of the tva receptor gene have already been found in in an ASLV subgroup A-resistant chicken line (32). The perfect analogy of receptor-disabling mutations and deletions in the critical ECL regions of XPR1 (7) and NHE1 (20; also this work) suggests that this is a common mechanism leading to host resistance to a virus.…”