Abstract
BackgroundFeline leukemia virus (FeLV)-945, a member of the FeLV-A subgroup, was previously isolated from a cohort of naturally infected cats. An unusual multicentric lymphoma of non-T-cell origin was observed in natural and experimental infection with FeLV-945. Previous studies implicated the FeLV-945 surface glycoprotein (SU) as a determinant of disease outcome by an as yet unknown mechanism. The present studies demonstrate that FeLV-945 SU confers distinctive properties of binding to the cell surface receptor.ResultsVirions bearing the FeLV-945 Env protein were observed to bind the cell surface receptor with significantly increased efficiency, as was soluble FeLV-945 SU protein, as compared to the corresponding virions or soluble protein from a prototype FeLV-A isolate. SU proteins cloned from other cohort isolates exhibited increased binding efficiency comparable to or greater than FeLV-945 SU. Mutational analysis implicated a domain containing variable region B (VRB) to be the major determinant of increased receptor binding, and identified a single residue, valine 186, to be responsible for the effect.ConclusionsThe FeLV-945 SU protein binds its cell surface receptor, feTHTR1, with significantly greater efficiency than does that of prototype FeLV-A (FeLV-A/61E) when present on the surface of virus particles or in soluble form, demonstrating a 2-fold difference in the relative dissociation constant. The results implicate a single residue, valine 186, as the major determinant of increased binding affinity. Computational modeling suggests a molecular mechanism by which residue 186 interacts with the receptor-binding domain through residue glutamine 110 to effect increased binding affinity. Through its increased receptor binding affinity, FeLV-945 SU might function in pathogenesis by increasing the rate of virus entry and spread in vivo, or by facilitating entry into a novel target cell with a low receptor density.
Highlights
Feline leukemia virus (FeLV)-945, a member of the FeLV-A subgroup, was previously isolated from a cohort of naturally infected cats
The results demonstrated that virus particles bearing FeLV-945 surface glycoprotein (SU) bind to the cell surface receptor significantly more efficiently than do particles bearing the FeLV-A/61E SU (p < 0.001; Figure 1)
While these studies suggest differential binding properties of the viruses examined, the experiment as performed cannot account for the possibility that FeLV SU may be present in higher amounts, or may be differentially displayed, on the surface of virus particles in a manner as to influence receptor binding affinity
Summary
Feline leukemia virus (FeLV)-945, a member of the FeLV-A subgroup, was previously isolated from a cohort of naturally infected cats. An unusual multicentric lymphoma of non-T-cell origin was observed in natural and experimental infection with FeLV-945. Previous studies implicated the FeLV-945 surface glycoprotein (SU) as a determinant of disease outcome by an as yet unknown mechanism. Feline leukemia virus (FeLV) is a naturally occurring gammaretrovirus that infects domestic cats. The predominant disease presentation in the cohort was a multicentric lymphoma of non-T-cell origin detected in twelve cases, one of which was the original source of FeLV-945. Members of FeLV-A are ecotropic in host range and utilize feTHTR1, a thiamine transporter on the target cell surface, as a receptor for entry [7]
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