The five highly related envelope subgroups of the avian sarcoma and leukosis viruses (ASLVs), subgroup A [ASLV(A)] to ASLV(E), are thought to have evolved from an ancestral envelope glycoprotein yet utilize different cellular proteins as receptors. Alleles encoding the subgroup A ASLV receptors (Tva), members of the low-density lipoprotein receptor family, and the subgroup B, D, and E ASLV receptors (Tvb), members of the tumor necrosis factor receptor family, have been identified and cloned. However, alleles encoding the subgroup C ASLV receptors (Tvc) have not been cloned. Previously, we established a genetic linkage between tvc and several other nearby genetic markers on chicken chromosome 28, including tva. In this study, we used this information to clone the tvc gene and identify the Tvc receptor. A bacterial artificial chromosome containing a portion of chicken chromosome 28 that conferred susceptibility to ASLV(C) infection was identified. The tvc gene was identified on this genomic DNA fragment and encodes a 488-amino-acid protein most closely related to mammalian butyrophilins, members of the immunoglobulin protein family. We subsequently cloned cDNAs encoding Tvc that confer susceptibility to infection by subgroup C viruses in chicken cells resistant to ASLV(C) infection and in mammalian cells that do not normally express functional ASLV receptors. In addition, normally susceptible chicken DT40 cells were resistant to ASLV(C) infection after both tvc alleles were disrupted by homologous recombination. Tvc binds the ASLV(C) envelope glycoproteins with low-nanomolar affinity, an affinity similar to that of binding of Tva and Tvb with their respective envelope glycoproteins. We have also identified a mutation in the tvc gene in line L15 chickens that explains why this line is resistant to ASLV(C) infection.Retroviruses require an interaction between the viral glycoproteins and a specific cell surface protein (receptor) to initiate entry into a cell (reviewed in references 32 and 56). The envelope glycoproteins of retroviruses are composed of trimers of two glycoproteins: the surface glycoprotein (SU), which contains the domains responsible for interaction with the host receptor, and the transmembrane glycoprotein (TM), which anchors SU to the membrane and mediates fusion of the viral and host membranes. The interaction of the SU glycoprotein with the host receptor usually involves multiple, noncontiguous determinants in both proteins that specify receptor choice and binding affinity and trigger a conformational change in the envelope glycoproteins that initiates the fusion process. Despite the complexity and specificity of the interaction between the viral glycoproteins and host receptors, closely related retroviruses carry envelope glycoproteins with mutations that alter receptor usage. The natural selection of retroviral subgroups with altered receptor usage may help the virus overcome host resistance and promote coinfection and may lead to heterotransmission.The five highly related envelope subgroups of...

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...

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A complex interaction between the retroviral envelope glycoproteins and a specific cell surface protein initiates viral entry into cells. The avian leukosis-sarcoma virus (ALV) group of retroviruses provides a useful experimental system for studying the retroviral entry process and the evolution of receptor usage. In this Retroviruses share a common overall strategy for entry into cells (for recent reviews, see references 26 and 40). The retroviral envelope glycoproteins are initially synthesized as a polyprotein precursor that is subsequently processed into two glycoproteins: the surface glycoprotein (SU), which contains the major domains that interact with the host receptor, and the transmembrane glycoprotein (TM), which anchors SU to the membrane and is directly involved in the fusion of viral and host membranes. The entry process is initiated by a complex interaction between SU and a specific cell surface protein that acts as a receptor, involving multiple, noncontiguous determinants in both proteins that specify receptor choice and binding affinity. Only a proper interaction triggers a conformational change in the structure of the viral glycoproteins which unlocks the fusion peptide located in TM. The exposed fusion peptide interacts with the target cell membrane, initiating a multistep process leading to fusion of the viral and cellular membranes and delivery of a subviral particle into the cell. Despite the complexity of the initial viral SU-cellular receptor interaction, retroviruses have the ability to evolve the structure of their envelope glycoproteins so that they can use a different cellular protein as a receptor (at times a protein that has no obvious homology to the original receptor) and retain efficient entry functions.The avian leukosis-sarcoma virus (ALV) group of retroviruses provides a useful experimental system for studying the initial interactions of retroviral entry and the evolution of receptor usage. ALV envelope subgroups A through E [ALV(A) through ALV(E)] are highly related, suggesting that these viruses have evolved from a common viral ancestor to use distinct cellular proteins as receptors in order to gain entry into chicken cells, presumably in response to the development of host resistance to viral entry. ALV(A) to ALV(E) SU glycoproteins are almost identical except for five hypervariable regions designated vr1, vr2, hr1, hr2, and vr3 ( Fig. 1) (6,7,13). Past analyses have suggested that the principal receptor interaction determinants are contained in the hr1 and hr2 domains of ALV SU, with vr3 playing a role in the specificity of receptor recognition but not in receptor binding affinity (14,36,37). The vr1 and vr2 hypervariable regions did not appear to be essential for receptor specificity or binding affinity.Five cell surface proteins have been identified as ALV receptors. The two subgroup A receptors, quail Tva and the chicken Tva homologue, are related to the low-density lipoprotein receptor family (4, 5, 41). The three receptors Tvb S1 (subgroups B, D, and E) (2), Tvb S3 (...