Article

Temporal modulation of an autoprotease is crucial for replication and pathogenicity of an RNA virus.

Institut für Virologie (FB Veterinärmedizin), Justus-Liebig-Universität Giessen, Frankfurter Strasse 107, 35392 Giessen, Germany.
Journal of Virology (impact factor: 5.4). 11/2004; 78(19):10765-75. DOI:10.1128/JVI.78.19.10765-10775.2004 pp.10765-75
Source: PubMed

ABSTRACT Pestiviruses belong to the family Flaviviridae, and their genome is a single-stranded RNA of positive polarity encoding one large polyprotein which is further processed into mature proteins. Noncytopathogenic (noncp) strains of the pestivirus bovine viral diarrhea virus (BVDV) can establish persistent infection. In persistently infected animals, noncp BVDVs occasionally acquire mutations in viral nonstructural protein 2 (NS2) that give rise to cytopathogenic (cp) BVDV variants, and, eventually, lead to the onset of lethal disease. A molecular marker of cp BVDV infection is a high-level expression of the replicative NS3 protease/helicase that together with NS2 is derived from NS2-3. Here, we present evidence for NS2-3 autoprocessing by a newly identified cysteine protease in NS2 that is distantly related to the NS2-3 autoprotease of hepatitis C and GB viruses. The vital role of this autoprotease in BVDV infection was established, implying an essential function for NS3 in pestiviral RNA replication which cannot be supplied by its NS2-3 precursor. Accordingly, and contrary to a current paradigm, we detected almost complete cleavage of NS2-3 in noncp BVDV at early hours of infection. At 6 to 9 h postinfection, NS2-3 autoprocessing diminished to barely detectable levels for noncp BVDV but decreased only moderately for cp BVDV. Viral RNA synthesis rates strictly correlated with different NS3 levels in noncp and cp BVDV-infected cells, implicating the NS2 autoprotease in RNA replication control. The biotype-specific modulation of NS2-3 autoprocessing indicates a crucial role of the NS2 autoprotease in the pathogenicity of BVDV.

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Keywords

9 h postinfection
 
BVDV infection
 
cp BVDV
 
cp BVDV infection
 
cp BVDV-infected cells
 
crucial role
 
hepatitis C
 
identified cysteine protease
 
noncp BVDV
 
noncp BVDVs
 
NS2-3 autoprocessing
 
NS2-3 precursor
 
persistent infection
 
pestiviral RNA replication
 
positive polarity encoding
 
replicative NS3 protease/helicase
 
RNA replication control
 
single-stranded RNA
 
viral nonstructural protein 2
 
vital role
 

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