Two Different Molecular Defects in the Tva Receptor Gene Explain the Resistance of Twotva^rLines of Chickens to Infection by Subgroup A Avian Sarcoma and Leukosis Viruses

Abstract

Retroviruses share a common strategy for entry into cells (reviewed in references 27 and 51). The entry process is initiated by an interaction between the viral envelope glycoprotein and a specific cell surface protein that acts as a receptor. This interaction triggers a conformational change in the structure of the viral glycoprotein that leads to the fusion of the viral and cellular membranes. Despite the complexity of the interaction between the viral glycoprotein and the receptor, closely related retroviruses carry envelope glycoproteins that use different cellular proteins as receptors. In the avian sarcoma and leukosis viruses (ASLVs), there are five highly related envelope subgroups, subgroups A to E, that are thought to have evolved from a common ancestor (reviewed in references 7 and 50). The presence of viral subgroups that utilize distinct receptors helps the virus overcome host resistance and promotes coinfection. We and others have developed strategies that mimic resistance to ASLV entry in cell culture to study the evolution of the envelope glycoprotein. These studies demonstrated that blocking virus entry could select viral variants with mutations in the viral glycoproteins that altered receptor usage (24,25,31,34,43). The goal of the present study was to identify and characterize the mutations in the subgroup A receptor in lines of chickens that cause resistance to infection by ASLVs carrying the subgroup A envelope glycoproteins.Three genetic loci in chicken cells determine the susceptibility and resistance to subgroup A to E ASLVs: tva (susceptibility to subgroup A viruses), tvb (susceptibility to subgroup B, D, and E viruses), and tvc (susceptibility to subgroup C viruses) (49, 50). Alleles that confer susceptibility to ASLV infection are dominant: two recessive resistance alleles are required at these loci to confer resistance. Because the tva r , tvb r , and tvc r resistance alleles are recessive, it is unlikely that these alleles encode dominant-negative forms of the receptor protein. The resistance alleles are likely to contain defects that either block receptor expression or prevent its use as an efficient ASLV receptor (29).Several alleles of the tvb genetic locus and three related Tvb receptors have been identified. Two different susceptibility alleles have been defined at the chicken tvb locus. The tvb s1 allele confers susceptibility to subgroups B, D, and E; the tvb s3 allele confers susceptibility to only subgroups B and D (1, 3). These alleles encode the chicken Tvb S1 (3) and Tvb S3 (12) receptors, respectively. Tvb S3 differs from Tvb S1 by a single amino acid change, cysteine to serine at position 62, which presumably alters the structure of the Tvb S1 protein so that it no longer functions as an ASLV(E) receptor. A third tvb receptor, the turkey Tvb T receptor (2), which confers susceptibility to only subgroup E ASLV, has also been cloned. The Tvb proteins are members of the tumor necrosis factor receptor (TNFR) family. The recessive tvb r resistance allele does not support the...

Quantitative imaging of endosome acidification and single retrovirus fusion with distinct pools of early endosomes

“…Subtype A ASLV envelope glycoprotein (EnvA) becomes competent to mediate low-pH-dependent membrane fusion only after binding to the avian tumor virus receptor A (TVA receptor) (22,23). Both isoforms of this receptor, the transmembrane (TVA950) and GPI-anchored (TVA800) proteins (24), support ASLV fusion but appear to direct the virus entry through different endocytic routes (13,14). To determine the timing and the strength of the pH trigger that activates the receptor-primed ASLV entering through different routes, we imaged fusion of triple-labeled pseudoviruses into cells expressing either TVA800 or TVA950.…”

Model of the TVA Receptor Determinants Required for Efficient Infection by Subgroup A Avian Sarcoma and Leukosis Viruses

“…1B) (28). Data previously presented by others determined that only the LDL-A region of TVA is necessary and sufficient to confer susceptibility to infection by ASLV(A) (23,26).…”

“…The construction of the chicken TVA expression plasmid pTvaS was described previously (28). In short, the sequence encoding the complete chicken TVA receptor was truncated in the intracellular tail, and a hemagglutinin tag and His 6 tag were added by PCR.…”

Na + /H + exchanger type 1 is a receptor for pathogenic subgroup J avian leukosis virus

“…For example, two different forms of the ALV-A receptor Tva, with either a cysteine-to-tryptophan change that abrogates EnvA binding or a frameshift that abolishes receptor expression, lead to genetic resistance to infection (31). Similarly, sequence variation in Tvb accounts for differential interactions with the subgroup B, D, and E Env proteins and susceptibility to the viruses carrying them (32).…”