Attenuation of Sindbis virus variants incorporating uncleaved PE2 glycoprotein is correlated with attachment to cell-surface heparan sulfate.
Sindbis virus virions incorporating uncleaved precursor envelope protein PE2 bind efficiently to cell-surface heparan sulfate (HS) because the furin cleavage site (a consensus HS-binding domain) is retained in the mature virus particle. However, they are essentially nonviable. Resuscitating mutations selected in the E3 or E2 protein preserve the PE2 noncleaving phenotype and HS binding, but facilitate fusion, and thereby restore wild-type infectivity on cultured cells. Here, we have demonstrated that the resuscitated PE2 noncleaving virus was almost avirulent in vivo, but mutated during the infection. Mutants had increased virulence and cleavage of PE2, with reduced HS binding capacity. We hypothesize that HS binding leads to sequestration of PE2 noncleaving virus particles and suppression of serum viremia, thereby selecting for evolution of the virus into a PE2-cleaving, low HS-binding phenotype.
Ryman
Kate D
KD
Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. kryman@lsuhsc.edu
Klimstra
William B
WB
Johnston
Robert E
RE
D018354:Alphavirus Infections / Q000378:metabolism / Q000821:virology*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D017354:Point Mutation; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012845:Sindbis Virus / Q000737:chemistry / Q000472:pathogenicity* / Q000502:physiology; D014759:Viral Envelope Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence / Q000235:genetics; D014779:Virus Replication
D019812:Heparan Sulfate Proteoglycans; D008562:Membrane Glycoproteins; D011498:Protein Precursors; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C064950:glycoprotein E2, Sindbis virus; C102373:glycoprotein PE2, Sindbis virus