Porcine circovirus
Encyclopedia
Porcine circovirus is a single-stranded DNA virus (class II), that is nonenveloped with an unsegmented circular genome. The viral capsid is icosahedral and approximately 17 nm in diameter. PCV is a member of the virus
family Circoviridae
.
PCVs are the smallest viruses replicating autonomously in eukaryotic cells. They replicate in the nucleus of infected cells, using the host polymerase for genome amplification.
There are 2 strains: type 1 and type 2.
PCV-1 (first identified in 1974) readily infects, but is not known to cause disease in swine; the type 2 has caused problems in recent years with the increasing occurrence of postweaning multisystemic wasting syndrome
(PMWS), which over time results in significant depletion of lymphocytes; postmortem examination of diseased animals reveals enlarged lymph nodes and abnormal lung tissue.
It is still unclear whether PCV-2 (first isolated in 1997) actually causes PMWS, as infection with the virus alone causes no clinical signs; it appears to work synergistically with parvovirus
, perhaps with parvovirus activating a latent form of circovirus or weakening the immune system enough for PCV to take hold. PCV-1 and PCV-2 show a high degree of sequence identity and a similar genomic organisation; nevertheless, the basis of the distinct pathogenicity has not yet been unravelled.
An effective vaccination is now available. Fort Dodge Animal Health (Wyeth
) launched the first USDA approved vaccine in 2006, containing an inactivated virus (ATCvet code: ).
The two replicase enzymes that are created from ORF1, Rep and Rep', are conserved between the two types of PCV, and are part of the early phase of the virus. The replicases differ in that Rep is the full ORF1 transcript of 312 amino acids, whereas Rep' is a truncated form of ORF1 as a result of splicing and is only 168 amino acids in length. The promoter for rep (Prep) contains an Interferon-Stimulated Response Element (ISRE) that suggests Rep and Rep' are regulated by cytokine involvement, and is probably a means for the virus to overcome the host's immune responses to infection. Rep and Rep' form a dimer that binds to two hexameric regions adjacent to the stem-loop, H1 and H2, which is required for replication. When the dimer binds to this region, the replicases cleave the loop region of the stem-loop and remain covalently bound to the H1 and H2 regions of the DNA, which becomes the 5' end of the DNA. The newly formed 3'OH end forms a primer using host RNA polymerase, which is then used by the host's DNA polymerase to begin transcription of the viral DNA via rolling circle replication . After the complementary DNA strand has been created, the stem region of the stem-loop forms a loose, non-hydrogen bonded, quadruplet DNA structure. This loosely associated structure can form short lived DNA-trimers which forms two templates for replication, as well as maintaining the nucleic integrity of the stem region of the stem-loop. The termination of the replication sequence has not been identified, yet, though there is evidence supporting that Rep also represses its own promoter, Prep, at
The ORF2 region encodes Cap, which differs slightly between PCV-1 and PCV-2. This variation within PCV may explain why PCV-1 is non-pathogenic, while PCV-2 is pathogenic. The promoter for this protein is located within ORF1, within the site where Rep' is truncated, and is splice from the same exon to the starting point of the ORF2 coding region and expressed during both early and late phases. This is the immunogenic region of the virus and is the primary area of research for creating a vaccine to treat PMWS.
(FDA) health authorities recommended doctors suspend using Rotarix, one of two vaccines licensed in the United States against rotavirus
, due to findings of viral DNA
contamination. An independent academic research team in San Francisco identified porcine circovirus-1 DNA in two lots of Rotarix, and follow-up work by GlaxoSmithKline
confirmed the contamination in working cells and the viral "seed" used Rotarix production, also confirming the material was likely present since the early stages of product development, including the clinical trial
s for FDA approval.
Testing of the other licensed vaccine against rotavirus infection, RotaTeq, has also detected some components of both PCV-1 and PCV-2. Porcine circovirus 1 is not known to cause disease in humans or other animals.
As of 8 June 2010, FDA has, based on a careful review of a variety of scientific information, determined it is appropriate for clinicians and public health professionals in the United States to use both Rotarix and RotaTeq vaccine.
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
family Circoviridae
Circoviridae
The Circoviridae are a family of viruses. These are small, relatively poorly-studied viruses, with circular, single-stranded DNA genomes of approximately one to four kilobases-Virology:...
.
PCVs are the smallest viruses replicating autonomously in eukaryotic cells. They replicate in the nucleus of infected cells, using the host polymerase for genome amplification.
There are 2 strains: type 1 and type 2.
PCV-1 (first identified in 1974) readily infects, but is not known to cause disease in swine; the type 2 has caused problems in recent years with the increasing occurrence of postweaning multisystemic wasting syndrome
Postweaning multisystemic wasting syndrome
Postweaning multisystemic wasting syndrome is a disease seen in domestic pigs. This disease causes illness in piglets, with clinical signs including progressive loss of body condition, visibly enlarged lymph nodes, difficulty in breathing, and sometimes diarrhea, pale skin, and jaundice...
(PMWS), which over time results in significant depletion of lymphocytes; postmortem examination of diseased animals reveals enlarged lymph nodes and abnormal lung tissue.
It is still unclear whether PCV-2 (first isolated in 1997) actually causes PMWS, as infection with the virus alone causes no clinical signs; it appears to work synergistically with parvovirus
Parvovirus
Parvovirus, often truncated to "parvo", is both the common name in English casually applied to all the viruses in the Parvoviridae taxonomic family, and also the taxonomic name of the Parvovirus genus within the Parvoviridae family...
, perhaps with parvovirus activating a latent form of circovirus or weakening the immune system enough for PCV to take hold. PCV-1 and PCV-2 show a high degree of sequence identity and a similar genomic organisation; nevertheless, the basis of the distinct pathogenicity has not yet been unravelled.
An effective vaccination is now available. Fort Dodge Animal Health (Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
) launched the first USDA approved vaccine in 2006, containing an inactivated virus (ATCvet code: ).
Genome
PCV's genome is one of the simplest of all viruses, requiring only a capsid protein (ORF2) and two replicase proteins (ORF1) in order to replicate and produce a functional virus. Due to the simplicity of PCV, it must rely heavily on the host's cellular machinery to replicate. The origin of replication is located on a small octanucleotide stem-loop that is flanked by palindromic repeats, with the ORF's being located head-to-head on both sides the Ori. Specifically, ORF1 is located clockwise and ORF2 is located counterclockwise of the Ori.The two replicase enzymes that are created from ORF1, Rep and Rep', are conserved between the two types of PCV, and are part of the early phase of the virus. The replicases differ in that Rep is the full ORF1 transcript of 312 amino acids, whereas Rep' is a truncated form of ORF1 as a result of splicing and is only 168 amino acids in length. The promoter for rep (Prep) contains an Interferon-Stimulated Response Element (ISRE) that suggests Rep and Rep' are regulated by cytokine involvement, and is probably a means for the virus to overcome the host's immune responses to infection. Rep and Rep' form a dimer that binds to two hexameric regions adjacent to the stem-loop, H1 and H2, which is required for replication. When the dimer binds to this region, the replicases cleave the loop region of the stem-loop and remain covalently bound to the H1 and H2 regions of the DNA, which becomes the 5' end of the DNA. The newly formed 3'OH end forms a primer using host RNA polymerase, which is then used by the host's DNA polymerase to begin transcription of the viral DNA via rolling circle replication . After the complementary DNA strand has been created, the stem region of the stem-loop forms a loose, non-hydrogen bonded, quadruplet DNA structure. This loosely associated structure can form short lived DNA-trimers which forms two templates for replication, as well as maintaining the nucleic integrity of the stem region of the stem-loop. The termination of the replication sequence has not been identified, yet, though there is evidence supporting that Rep also represses its own promoter, Prep, at
The ORF2 region encodes Cap, which differs slightly between PCV-1 and PCV-2. This variation within PCV may explain why PCV-1 is non-pathogenic, while PCV-2 is pathogenic. The promoter for this protein is located within ORF1, within the site where Rep' is truncated, and is splice from the same exon to the starting point of the ORF2 coding region and expressed during both early and late phases. This is the immunogenic region of the virus and is the primary area of research for creating a vaccine to treat PMWS.
Entry
PCV infects a wide variety of cell types, including hepatocytes, cardiomyocytes, and macrophages. However, until recently, it was unknown exactly how attachment and entry into these cells was achieved. Research has shown that PCV utilizes clatherin-mediated endocytosis to enter the cell, though it's stipulated that there may still be other factors that haven't been identified. Once endocytosed, the endosome and lysosome formation causes an acidic p.H. shift, which allows ATP-driven uncoating of the virus and allows it to escape the endosomes and lysosomes. After which, The virus travels to the nucleus through unknown means.Escape
Besides ORF1 and ORF2, there is also an ORF3 which is not necessarily required for PCV to survive within the host. Research has shown that the protein coded in ORF3 can modulate the host cell's cell division cycle and cause cell-mediated, virus-induced apoptosis. Using a yeast two-hybrid screening system of ORF3 against the porcine cDNA library indicated that the ORF3 protein interacts with the porcine pPirh2, which is a E3 ubquitin ligase. This E3 ubquitin ligase normally interacts with p53 during the cell division cycle and prevents it from halting the cell division cycle at S-phase. However, ORF3 also interacts with pPirh2 at the same region as p53 and causes an upregulation of p53 expression. This increase in p53 stops the cell division cycle and the result of this is p53 mediated apoptosis, which releases PCV into the extracellular environment.Porcine circovirus DNA identified in human vaccine
On 22 March 2010, U.S. Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) health authorities recommended doctors suspend using Rotarix, one of two vaccines licensed in the United States against rotavirus
Rotavirus
Rotavirus is the most common cause of severe diarrhoea among infants and young children, and is one of several viruses that cause infections often called stomach flu, despite having no relation to influenza. It is a genus of double-stranded RNA virus in the family Reoviridae. By the age of five,...
, due to findings of viral DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
contamination. An independent academic research team in San Francisco identified porcine circovirus-1 DNA in two lots of Rotarix, and follow-up work by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
confirmed the contamination in working cells and the viral "seed" used Rotarix production, also confirming the material was likely present since the early stages of product development, including the clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s for FDA approval.
Testing of the other licensed vaccine against rotavirus infection, RotaTeq, has also detected some components of both PCV-1 and PCV-2. Porcine circovirus 1 is not known to cause disease in humans or other animals.
As of 8 June 2010, FDA has, based on a careful review of a variety of scientific information, determined it is appropriate for clinicians and public health professionals in the United States to use both Rotarix and RotaTeq vaccine.
External links
- The Control of Porcine Circovirus Diseases (PCVDs): Towards Improved Food Quality and Safety
- Animal Disease Diagnostic Laboratory
- Porcine Circovirus Type 2
- Swine health fact sheet
- The Economics of PMWS - Porc Quebec Magazine Article
- Animal viruses
- Stopcircovirus.com
- Viralzone: Circovirus
- Articles by Quim Segalés on PCV2 - pig333.com