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.