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

Abstract

The study of the interactions of subgroup A avian sarcoma and leucosis viruses [ASLV(A)] with the TVA receptor required to infect cells offers a powerful experimental model of retroviral entry. Several regions and specific residues in the TVA receptor have previously been identified to be critical determinants of the binding affinity with ASLV(A) envelope glycoproteins and to mediate efficient infection. Two homologs of the TVA receptor have been cloned: the original quail TVA receptor, which has been the basis for most of the initial characterization of the ASLV(A) TVA, and the chicken TVA receptor, which is 65% identical to the quail receptor overall but identical in the region thought to be critical for infection. Our previous work characterized three mutant ASLV(A) isolates that could efficiently bind and infect cells using the chicken TVA receptor homolog but not using the quail TVA receptor homolog, with the infectivity of one mutant virus being >500-fold less with the quail TVA receptor. The mutant viruses contained mutations in the hr1 region of the surface glycoprotein. Using chimeras of the quail and chicken TVA receptors, we have identified new residues of TVA critical for the binding affinity and entry of ASLV(A) using the mutant glycoproteins and viruses to probe the function of those residues. The quail TVA receptor required changes at residues 10, 14, and 31 of the corresponding chicken TVA residues to bind wild-type and mutant ASLV(A) glycoproteins with a high affinity and recover the ability to mediate efficient infection of cells. A model of the TVA determinants critical for interacting with ASLV(A) glycoproteins is proposed. IMPORTANCE A detailed understanding of how retroviruses enter cells, evolve to use new receptors, and maintain efficient entry is crucial for identifying new targets for combating retrovirus infection and pathogenesis, as well as for developing new approaches for targeted gene delivery.Since all retroviruses share an envelope glycoprotein organization, they likely share a mechanism of receptor triggering to begin the entry process. Multiple, noncontiguous interaction determinants located in the receptor and the surface (SU) glycoprotein hypervariable domains are required for binding affinity and to restrict or broaden receptor usage. In this study, further mechanistic details of the entry process were elucidated by characterizing the ASLV(A) glycoprotein interactions with the TVA receptor required for entry. The ASLV(A) envelope glycoproteins are organized into functional domains that allow changes in receptor choice to occur by mutation and/or recombination while maintaining a critical level of receptor binding affinity and an ability to trigger glycoprotein conformational changes. For enveloped viruses to infect cells, they must fuse their viral membrane with a cellular membrane. For retroviruses, the interaction of the viral envelope glycoproteins with a cellular surface protein receptor initiates the entry and fusion process (1, 2). Retroviral envelope glycopro...

Reverse Engineering Provides Insights on the Evolution of Subgroups A to E Avian Sarcoma and Leukosis Virus Receptor Specificity

“…However, a genetic evolution experimental system selected ASLV(A) variants with mutations in the envelope glycoproteins that could now preferentially use the chicken Tva receptor with high binding affinity and infection efficiency but not the quail Tva homolog [22,23,45]. Several critical residues in the amino-terminal half of Tva were found to account for this preference: residues at positions 11, 14, and 31 [46].…”

Mutations in Both the Surface and Transmembrane Envelope Glycoproteins of the RAV-2 Subgroup B Avian Sarcoma and Leukosis Virus Are Required to Escape the Antiviral Effect of a Secreted Form of the TvbS3 Receptor †

“…Members of three very different families of proteins have been identified to be receptors of these five ASLVs, although all are simple, single-spanning membrane proteins. Tva proteins are related to low density lipoprotein receptors (LDLR) and are receptors for ASLV(A) [13,14,15]. Tvb proteins are related to tumor necrosis factor receptors and are receptors for ASLV(B), ASLV(D) and ASLV(E) [16,17,18,19].…”

Comparison of Viremia, Cloacal Virus Shedding, Antibody Responses and Pathological Lesions in Adult Chickens, Quails, and Pigeons Infected with ALV-A

“…Some studies confirmed that quails possess the receptor TVA, which can recognize ALV-A 33,34 ; however, this receptor is 65% homologous to that of chickens and has a lower affinity for ALV-A 35 . A charged second-site mutation in some amino acids of quail TVA can increase their affinity and susceptibility to ALV-A 36,37 . Differences in ALV receptor affinity could partly explain the difference in susceptibility to ALV-A between quails and chickens.…”