Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

Stewart, H., Adema, K. W., McMonagle, E. L., Hosie, M. J. and Willett, B. J. (2012) Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus. Retrovirology, 9, 48. (doi:10.1186/1742-4690-9-48) (PMID:22650160) (PMCID:PMC3403869)

[img]
Preview
Text
67914.pdf - Published Version

510kB

Abstract

<b>BACKGROUND:</b> The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.<p></p> <b>RESULTS:</b> Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.<p></p> <b>CONCLUSIONS:</b> Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stewart, Ms Hazel and Hosie, Professor Margaret and Willett, Professor Brian and McMonagle, Mrs Elizabeth
Authors: Stewart, H., Adema, K. W., McMonagle, E. L., Hosie, M. J., and Willett, B. J.
Subjects:Q Science > QR Microbiology > QR355 Virology
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Retrovirology
Publisher:BioMed Central
ISSN:1742-4690
ISSN (Online):1742-4690
Published Online:31 May 2012
Copyright Holders:Copyright © 2012 Stewart et al.
First Published:First published in Retrovirology 9:48
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
363381Rational Design of a Lentiviral VaccineMargaret HosieMedical Research Council (MRC)G0300387/66515MVLS III - CENTRE FOR VIRUS RESEARCH
617571Identification of a novel viral agent in feline immunodeficiency virus (FIV)-associated lymphomagenesis (ISSF Catalyst Fund)Brian WillettWellcome Trust (WELLCOME)097821/Z/11/ZMVLS III - CENTRE FOR VIRUS RESEARCH