Removal of either N-glycan site from the envelope receptor binding domain of Moloney and Friend but not AKV mouse ecotropic gammaretroviruses alters receptor usage

Knoper, Ryan C.; Ferrarone, John R.; Yan, Yong-Bin; Lafont, Bernard A. P.; Kozak, Christine A.

doi:10.1016/j.virol.2009.06.015

Cited by 8 publications

(6 citation statements)

References 38 publications

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“…We demonstrated that this disadvantage comes from a less efficient early infection and less efficient virus replication and/or spread. The detrimental consequence of N-glycan deletion on virus infectivity has been extensively studied with HIV [60], [61], [62] and other viruses [63], [64]. However, to the best of our knowledge, no studies have looked at the effect of N-glycan deletion on virus infectivity in neurons.…”

Section: Discussionmentioning

confidence: 99%

LCMV Glycosylation Modulates Viral Fitness and Cell Tropism

Knopp

Bederka

et al. 2013

PLoS ONE

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The glycoprotein (GP) of arenaviruses is glycosylated at 11 conserved N-glycosylation sites. We constructed recombinant lymphocytic choriomeningitis virus (rLCMV) featuring either additions or deletions of these N-glycans to investigate their role in the viral life cycle. N-glycosylation at two sites, T87 and S97, were found to be necessary to rescue rLCMV. Three of nine successfully rescued mutants, S116A, T234A, and S373A, under selective pressures in either epithelial, neuronal, or macrophage cells reverted to WT sequence. Of the seven stable N-glycan deletion mutants, five of these led to altered viral fitness and cell tropism, assessed as growth in either mouse primary cortical neurons or bone marrow derived macrophages. These results demonstrate that the deletion of N-glycans in LCMV GP may confer an advantage to the virus for infection of neurons but a disadvantage in macrophages.

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Section: Discussionmentioning

confidence: 99%

LCMV Glycosylation Modulates Viral Fitness and Cell Tropism

Knopp

Bederka

et al. 2013

PLoS ONE

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“…It has been shown that loss of MoMLV gs2 results in a virus that is temperature sensitive in Rat2 cells, loss of gs4 produces noninfectious virus lacking SU protein, and loss of gs7 alters fusion and infectivity [ 70 – 73 ]. Removal of either of the 2 glycosylation sites in the Env RBD, gs1 and gs2, can produce viruses restricted by M. dunni cells due to altered virus binding to dCAT-1, although E-MLVs differ in their reliance on these glycans [ 74 , 75 ]. Thus, N-linked glycans on the viral Env are required for proper folding and can influence the entry process, while glycans are not needed for CAT-1 receptor processing or receptor function and have, at best, limited ability to modulate virus entry.…”

Section: The Role Of Glycosylation In E-mlv Entry and Tropismmentioning

confidence: 99%

Naturally Occurring Polymorphisms of the Mouse Gammaretrovirus Receptors CAT-1 and XPR1 Alter Virus Tropism and Pathogenicity

Kozak

2011

Advances in Virology

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Gammaretroviruses of several different host range subgroups have been isolated from laboratory mice. The ecotropic viruses infect mouse cells and rely on the host CAT-1 receptor. The xenotropic/polytropic viruses, and the related human-derived XMRV, can infect cells of other mammalian species and use the XPR1 receptor for entry. The coevolution of these viruses and their receptors in infected mouse populations provides a good example of how genetic conflicts can drive diversifying selection. Genetic and epigenetic variations in the virus envelope glycoproteins can result in altered host range and pathogenicity, and changes in the virus binding sites of the receptors are responsible for host restrictions that reduce virus entry or block it altogether. These battleground regions are marked by mutational changes that have produced 2 functionally distinct variants of the CAT-1 receptor and 5 variants of the XPR1 receptor in mice, as well as a diverse set of infectious viruses, and several endogenous retroviruses coopted by the host to interfere with entry.

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“…This phenotype reflects how the mutation/sugar addition restricted Env's interactions with the dCAT-1 version of the ecotropic receptor. The mutation changes are again distinct from those residues in the RBD, which have been previously demonstrated to be associated with unique interactions with dCAT-1 (53,54). Moreover, the gs5 site is a considerable distance from the amino acid residues known to be critical for Env-mCAT-1 binding (S118 and D120) (Fig.…”

Section: Discussionmentioning

confidence: 61%

Unique N-Linked Glycosylation of CasBrE Env Influences Its Stability, Processing, and Viral Infectivity but Not Its Neurotoxicity

Renszel

Traister

Lynch

2013

J Virol

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bThe envelope protein (Env) from the CasBrE murine leukemia virus (MLV) can cause acute spongiform neurodegeneration analogous to that induced by prions. Upon central nervous system (CNS) infection, Env is expressed as multiple isoforms owing to differential asparagine (N)-linked glycosylation. Because N-glycosylation can affect protein folding, stability, and quality control, we explored whether unique CasBrE Env glycosylation features could influence neurovirulence. CasBrE Env possesses 6/8 consensus MLV glycosylation sites (gs) but is missing gs3 and gs5 and contains a putative site (gs*). Twenty-nine mutants were generated by modifying these three sites, individually or in combination, to mimic the amino acid sequence in the nonneurovirulent Friend 57 MLV. Three basic viral phenotypes were observed: replication defective (dead; titer < 1 focus-forming unit [FFU]/ml), replication compromised (RC) (titer ‫؍‬ 10 2 to 10 5 FFU/ml); and wild-type-like (WTL) (titer > 10 5 FFU/ml). Env protein was undetectable in dead mutants, while RC and WTL mutants showed variations in Env expression, processing, virus incorporation, virus entry, and virus spread. The newly introduced gs3 and gs5 sites were glycosylated, whereas gs* was not. Six WTL mutants tested in mice showed no clear attenuation in disease onset or severity versus controls. Furthermore, three RC viruses tested by neural stem cell (NSC)-mediated brainstem dissemination also induced acute spongiosis. Thus, while unique N-glycosylation affected structural features of Env involved in protein stability, proteolytic processing, and virus assembly and entry, these changes had minimal impact on CasBrE Env neurotoxicity. These findings suggest that the Env protein domains responsible for spongiogenesis represent highly stable elements upon which the more variable viral functional domains have evolved.

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Removal of either N-glycan site from the envelope receptor binding domain of Moloney and Friend but not AKV mouse ecotropic gammaretroviruses alters receptor usage

Cited by 8 publications

References 38 publications

LCMV Glycosylation Modulates Viral Fitness and Cell Tropism

LCMV Glycosylation Modulates Viral Fitness and Cell Tropism

Naturally Occurring Polymorphisms of the Mouse Gammaretrovirus Receptors CAT-1 and XPR1 Alter Virus Tropism and Pathogenicity

Unique N-Linked Glycosylation of CasBrE Env Influences Its Stability, Processing, and Viral Infectivity but Not Its Neurotoxicity

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