A Single-Amino-Acid Substitution in the Tvb ^S1 Receptor Results in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroups B and D and Resistance to Infection by Subgroup E In Vitro and In Vivo

Abstract

The avian sarcoma and leukosis virus (ASLV) family of retroviruses contains five highly related envelope subgroups (A to E) thought to have evolved from a common viral ancestor in the chicken population. Three genetic loci in chickens determine the susceptibility or resistance of cells to infection by the subgroup A to E ASLVs. Some inbred lines of chickens display phenotypes that are somewhere in between either efficiently susceptible or resistant to infection by specific subgroups of ASLV. The tvb gene encodes the receptor for subgroups B, D, and E ASLVs. The wild-type Tvb S1 receptor confers susceptibility to subgroups B, D, and E ASLVs. In this study, the genetic defect that accounts for the altered susceptibility of an inbred chicken Retroviruses cause serious diseases in animals and humans. The disease process begins with the virus infecting a cell(s), a process mediated by the interaction of the retroviral envelope glycoproteins with specific cell surface proteins that act as receptors (14,24). A proper viral-glycoprotein-receptor interaction initiates conformational changes in the viral glycoproteins that ultimately result in the fusion of the viral and cellular membranes and entry of viral components (9). Despite the complexity and specificity of the viral-glycoprotein-receptor interaction required for virus entry, families of closely related retroviruses have evolved their glycoproteins to use different cellular proteins as receptors. Presumably, the presence of multiple viral subgroups that utilize different receptors is an advantage for viruses in overcoming host resistance. Resistance to retroviral infection occurs when the specific receptor protein is not available. Genetic alteration(s) can account for resistance, resulting in the complete lack of receptor protein expression or the expression of an aberrant protein not suitable as a viral receptor. In addition, receptors can be saturated with viral glycoproteins expressed by the cell, physically blocking receptor accessibility, a phenomenon known as receptor interference (14, 24).The avian sarcoma and leukosis virus (ASLV) family of retroviruses contains five highly related envelope subgroups (A to E) thought to have evolved in the chicken population from a common viral ancestor (4,5,24). Three genetic loci in chickens determine the susceptibility or resistance of cells to infection by the subgroup A to E ASLVs. Susceptibility to subgroup A ASLVs is determined by the tva locus; susceptibility to subgroup C ASLVs by the tvc locus; and susceptibility to the subgroup B, D, and E ASLVs by the tvb locus. The Tva proteins are related to the low-density lipoprotein receptor family (6, 25). The Tvb proteins are related to the tumor necrosis factor receptor (TNFR) family (2, 3, 7). The Tvc proteins are most closely related to mammalian butyrophilins of the immunoglobulin superfamily (11). The normal functions and ligands of the Tva, Tvb, and Tvc proteins in birds are unknown.The genetic defects that account for resistance to infection by specific ASLVs, tv...

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

“…As a control, we inoculated five chicks of the line CC.R1 with subgroup A ASV. No infected CC.R1 chicken produced detectable sarcoma (Table 1), confirming the purity of the subgroup A ASV stock because line CC.R1 is resistant to the A subgroup (13) and sensitive to the B, C, and D subgroups (35).…”

“…We previously identified a singleamino-acid substitution in the Tvb receptor that resulted in reduced susceptibility to ASLV subgroups B and D and resistance to subgroup E (35). This finding implies the existence of similar genetic variations within other ASLV receptor loci, and inbred lines of domestic chicken can manifest the phenotype of such recessive alleles.…”

“…In conclusion, we demonstrated inefficient infection and slow spread of the ALV A subgroup in line P and G. g. murghi in vitro. This resembles the decreased susceptibility for the ALV B subgroup in line M (35).…”

“…This finding implies the existence of similar genetic variations within other ASLV receptor loci, and inbred lines of domestic chicken can manifest the phenotype of such recessive alleles. We therefore analyzed the susceptibility to the subgroup A ASLV in the panel of 12 inbred and close-bred chicken lines available at the Institute of Molecular Genetics in Prague (33) and, for comparison, the Indian red jungle fowl (G. g. murghi) in an in vitro kinetic assay (35). CEFs of defined origin were infected with replication-competent reporter ASLV vector RCASBP(A)GFP, and the percentage of GFP-positive cells was quantified by flow cytometry on seven subsequent days.…”

“…Whereas escape mutants of ASLVs with expanded viral receptor usage were already selected on cocultivated permissive and nonpermissive cells (34,38) or exerted by the presence of soluble competitor Tva (27), the natural occurrence of receptor variants with decreased susceptibility to ASLV infection remains to be explored. As a proof of the principle, we have identified a singleamino-acid substitution in the Tvb receptor that results in reduced susceptibility to ASLV subgroups B and D and resistance to subgroup E (35).…”