PMID- 26889041
OWN - NLM
STAT- MEDLINE
DCOM- 20160824
LR  - 20181113
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 90
IP  - 9
DP  - 2016 May
TI  - The Attenuation Phenotype of a Ribavirin-Resistant Porcine Reproductive and 
      Respiratory Syndrome Virus Is Maintained during Sequential Passages in Pigs.
PG  - 4454-4468
LID - 10.1128/JVI.02836-15 [doi]
AB  - In a previous study, ribavirin-resistant porcine reproductive and respiratory 
      syndrome virus (PRRSV) mutants (RVRp13 and RVRp22) were selected, and their 
      resistance against random mutation was shown in cultured cells. In the present 
      study, these ribavirin-resistant mutants were evaluated in terms of their genetic 
      and phenotypic stability during three pig-to-pig passages in comparison with 
      modified live virus (MLV) (Ingelvac PRRS MLV). Pigs challenged with RVRp22 had 
      significantly lower (P< 0.05) viral loads in sera and tissues than pigs 
      challenged with MLV or RVRp13 at the first passage, and the attenuated 
      replication of RVRp22 was maintained until the third passage. Viral loads in sera 
      and tissues dramatically increased in pigs challenged with MLV or RVRp13 during 
      the second passage. Consistently, all five sequences associated with the 
      attenuation of virulent PRRSV in RVRp13 and MLV quickly reverted to wild-type 
      sequences during the passages, but two attenuation sequences were maintained in 
      RVRp22 even after the third passage. In addition, RVRp22 showed a significantly 
      lower (P< 0.001) mutation frequency in nsp2, which is one of the most variable 
      regions in the PRRSV genome, than MLV. Nine unique mutations were found in open 
      reading frames (ORFs) 1a, 2, and 6 in the RVRp22 genome based on full-length 
      sequence comparisons with RVRp13, VR2332 (the parental virus of RVRp13 and 
      RVRp22), and MLV. Based on these results, it was concluded that RVRp22 showed 
      attenuated replication in pigs; further, because of the high genetic stability of 
      RVRp22, its attenuated phenotype was stable even after three sequential passages 
      in pigs. IMPORTANCE: PRRSV is a rapidly evolving RNA virus. MLV vaccines are 
      widely used to control PRRS; however, there have been serious concerns regarding 
      the use of MLV as a vaccine virus due to the rapid reversion to virulence during 
      replication in pigs. As previously reported, ribavirin is an effective antiviral 
      drug against many RNA viruses. Ribavirin-resistant mutants reemerged by escaping 
      lethal mutagenesis when the treatment concentration was sublethal, and those 
      mutants were genetically more stable than parental viruses. In a previous study, 
      two ribavirin-resistant PRRSV mutants (RVRp13 and RVRp22) were selected, and 
      their higher genetic stability was shown in vitro Consequently, in the present 
      study, both of the ribavirin-resistant mutants were evaluated in terms of their 
      genetic and phenotypic stability in vivo RVRp22 was found to exhibit higher 
      genetic and phenotypic stability than MLV, and nine unique mutations were 
      identified in the RVRp22 genome based on a full-length sequence comparison with 
      the RVRp13, VR2332, and MLV genomes.
CI  - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved.
FAU - Khatun, Amina
AU  - Khatun A
AD  - College of Veterinary Medicine, Chonbuk National University, Iksan, South Korea.
FAU - Shabir, Nadeem
AU  - Shabir N
AD  - College of Veterinary Medicine, Chonbuk National University, Iksan, South Korea.
FAU - Seo, Byoung-Joo
AU  - Seo BJ
AD  - College of Veterinary Medicine, Chonbuk National University, Iksan, South Korea.
FAU - Kim, Bum-Seok
AU  - Kim BS
AD  - College of Veterinary Medicine, Chonbuk National University, Iksan, South Korea.
FAU - Yoon, Kyoung-Jin
AU  - Yoon KJ
AD  - College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA.
FAU - Kim, Won-Il
AU  - Kim WI
AUID- ORCID: 0000-0002-0465-0794
AD  - College of Veterinary Medicine, Chonbuk National University, Iksan, South Korea 
      kwi0621@jbnu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160414
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antibodies, Viral)
RN  - 0 (Antiviral Agents)
RN  - 0 (Immunoglobulin G)
RN  - 49717AWG6K (Ribavirin)
SB  - IM
MH  - Animals
MH  - Antibodies, Viral/blood/immunology
MH  - Antiviral Agents/*pharmacology
MH  - Cell Line
MH  - *Drug Resistance, Viral
MH  - Genome, Viral
MH  - Immunoglobulin G/blood/immunology
MH  - Microbial Sensitivity Tests
MH  - Mutation
MH  - Mutation Rate
MH  - Open Reading Frames
MH  - *Phenotype
MH  - Porcine Reproductive and Respiratory Syndrome/pathology/*virology
MH  - Porcine respiratory and reproductive syndrome virus/*drug effects/physiology
MH  - Ribavirin/*pharmacology
MH  - Swine
MH  - Viral Load
MH  - Viremia
MH  - Virulence/genetics
MH  - Virus Replication/drug effects
PMC - PMC4836337
EDAT- 2016/02/19 06:00
MHDA- 2016/08/25 06:00
PMCR- 2016/10/14
CRDT- 2016/02/19 06:00
PHST- 2015/11/07 00:00 [received]
PHST- 2016/02/12 00:00 [accepted]
PHST- 2016/02/19 06:00 [entrez]
PHST- 2016/02/19 06:00 [pubmed]
PHST- 2016/08/25 06:00 [medline]
PHST- 2016/10/14 00:00 [pmc-release]
AID - JVI.02836-15 [pii]
AID - 02836-15 [pii]
AID - 10.1128/JVI.02836-15 [doi]
PST - epublish
SO  - J Virol. 2016 Apr 14;90(9):4454-4468. doi: 10.1128/JVI.02836-15. Print 2016 May.