Mechanisms of Avian Retroviral Host Range Extension

Abstract

Alpharetroviruses provide a useful system for the study of the molecular mechanisms of host range and receptor interaction. These viruses can be divided into subgroups based on diverse receptor usage due to variability within the two host range determining regions, hr1 and hr2, in their envelope glycoprotein SU (gp85). In previous work, our laboratory described selection from a subgroup B avian sarcoma-leukosis virus of an extended-host-range variant (LT/SI) with two adjacent amino acid substitutions in hr1. This virus retains its ability to use the subgroup BD receptor but can also infect QT6/BD cells, which bear a related subgroup E receptor (R. A. Taplitz and J. M. Coffin, J. Virol 71:7814-7819, 1997). Here, we report further analysis of this unusual variant. First, one (L154S) of the two substitutions is sufficient for host range extension, while the other (T155I) does not alter host range. Second, these mutations extend host range to non-avian cell types, including human, dog, cat, mouse, rat, and hamster. Third, interference experiments imply that the mutants interact efficiently with the subgroup BD receptor and possibly the related subgroup E receptor, but they have another means of entry that is not dependent on these interactions. Fourth, binding studies indicate that the mutant SU proteins retain the ability to interact as monomers with subgroup BD and BDE receptors but only bind the subgroup E receptor in the context of an Env trimer. Further, the mutant SU proteins bind well to chicken cells but do not bind any better than wild-type subgroup B to QT6 or human cells, even though the corresponding viruses are capable of infecting these cells.Alpharetroviruses, or avian sarcoma-leukosis viruses (ASLVs), display a great deal of diversity in their envelope glycoprotein (Env) sequences leading to diverse host range but, with the exception of the long terminal repeat (LTR), are nearly identical throughout the remainder of their genomes (11, 15, 16, 25-27, 29, 42). This pattern suggests a response to selective pressures to replicate in a variety of hosts. Alpharetroviruses are divided into subgroups (A to J) depending on host range, superinfection resistance patterns, and neutralizing antibody cross-reactivity. The surface (SU) subunit of the envelope glycoprotein is responsible for receptor recognition. Through a poorly characterized process, probably requiring a low-pH step (34), the SU-receptor interaction triggers the transmembrane (TM) subunit to mediate fusion between the viral envelope and the target cell membrane (10,26,48).Receptors for ASLV of subgroups A, B, D, and E have been cloned. The receptor for subgroup A viruses is a low-density lipoprotein receptor-like protein and is unrelated to any other known retroviral receptor (5, 51). The receptors for B, D, and E are encoded by orthologous genes in the tumor necrosis factor receptor family (2,3,8,40). Chickens have two alleles capable of acting as the receptor for these viruses. , conferring susceptibility to infection by subgroup E but not subgr...

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

“…The selection of resistance alleles to ASLVs may also be hampered by the ability of retroviruses to evolve the structure of their envelope glycoproteins to alter their receptor usage. A variety of studies have demonstrated that ASLV can acquire mutations that alter the envelope and the viral host range (24,25,31,34,43). Subgroups of highly related viruses that use different proteins as receptors may vary the selective pressure to make it difficult for chickens to develop complete resistance to ASLV entry.…”

“…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.…”

Identification of Two Residues within the LDL-A Module of Tva That Dictate the Altered Receptor Specificity of Mutant Subgroup A Avian Sarcoma and Leukosis Viruses

“…One strategy is likely via high-affinity binding between the viral glycoproteins and the receptors. In contrast, another strategy is that mutations in viral glycoproteins allow the infection of diverse host cells without an evident increase in receptor binding (20). In this report, we have shown large differences in viral entry between quail and chicken LDL-A modules for the mutant viruses Y142N, E149K, and Y142N/E149K (see Table 1), but we were unable to observe corresponding differences in binding between quail and chicken LDL-A with the mutant envelope proteins (data not shown).…”

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

“…Subsequent accommodation of envelope proteins can result in complete changes of receptor usage and cellular tropism. 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).…”