Mutation of a Single Envelope N-Linked Glycosylation Site Enhances the Pathogenicity of Bovine Leukemia Virus

Viruses have coevolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants a...

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Bibliographic Details
Published in:Journal of virology 2015-09, Vol.89 (17), p.8945-8956
Main Authors: de Brogniez, Alix, Bouzar, Amel Baya, Jacques, Jean-Rock, Cosse, Jean-Philippe, Gillet, Nicolas, Callebaut, Isabelle, Reichert, Michal, Willems, Luc
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Base Sequence
Biochemistry, biophysics & molecular biology
Biochimie, biophysique & biologie moléculaire
Bovine leukemia virus
Cats
Cell Fusion
Cercopithecus aethiops
COS Cells
Glycosylation
HEK293 Cells
HeLa Cells
Humans
Hyperpathogenicity
Leukemia Virus, Bovine - genetics
Leukemia Virus, Bovine - metabolism
Leukemia Virus, Bovine - pathogenicity
Life Sciences
Membrane Fusion - genetics
Mutation
N-Glycosylation
Pathogenesis and Immunity
Protein Stability
Sciences du vivant
Sequence Alignment
Sequence Analysis, RNA
Sheep
Viral Envelope Proteins - genetics
Viral Envelope Proteins - metabolism
Viral Load
Virus Replication - genetics
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Summary:Viruses have coevolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants after latency periods of several years. In principle, the equilibrium reached between the virus and its host could be disrupted by emergence of more pathogenic strains. Intriguingly but fortunately, such a hyperpathogenic BLV strain was never observed in the field or designed in vitro. In this study, we sought to understand the role of envelope N-linked glycosylation with the hypothesis that this posttranslational modification could either favor BLV infection by allowing viral entry or allow immune escape by using glycans as a shield. Using reverse genetics of an infectious molecular provirus, we identified a N-linked envelope glycosylation site (N230) that limits viral replication and pathogenicity. Indeed, mutation N230E unexpectedly leads to enhanced fusogenicity and protein stability. Infection by retroviruses requires the interaction of the viral envelope protein (SU) with a membrane-associated receptor allowing fusion and release of the viral genomic RNA into the cell. We show that N-linked glycosylation of the bovine leukemia virus (BLV) SU protein is, as expected, essential for cell infection in vitro. Consistently, mutation of all glycosylation sites of a BLV provirus destroys infectivity in vivo. However, single mutations do not significantly modify replication in vivo. Instead, a particular mutation at SU codon 230 increases replication and accelerates pathogenesis. This unexpected observation has important consequences in terms of disease control and managing.
ISSN:0022-538X
1098-5514
1098-5514
DOI:10.1128/jvi.00261-15