]Polyomaviridae
Humans and
Viruses 2008, Stanford University
Created By Stacie
Vilendrer
Image of Simian
Virus 40. Public Domain.
Welcome to the Polyomaviridae viral family
webpage! This is only one of a
series of student-produced websites on the various viral families as a part of
Dr. Robert SiegelÕs Humans and Viruses course at Stanford University. Whether you are a virology neophyte or connoisseur,
you are bound to quench your polydipsia for polyomaviridae as you read on. Check out your options below!
|
1.
Polyomaviridae gets its name because it causes many (poly) tumors (omas) in many
of itÕs hosts. 2.
Polyomaviridae used to be a part of a family
called Papovaviridae which also included Papilloma. The family split in 2000 based on structural
and replication differences. 3.
Polyomaviridae was discovered in 1950 by a team of
researchers, and mouse polyomavirus was subsequently used to study viral DNA
tumors. 4.
Polyomaviruses infect warm-blooded vertebrates including
both mammals (humans, monkeys, cattle, rabbits, rats, mice, and hamsters) and
birds (parakeets, geese, and others).
5.
There are currently about 14 known viruses but many
continue to be discovered. 6.
Clinical outcome can vary—most are asymptomatic in native
hosts but can cause severe or lethal tumors in other hosts. 7.
Avian viruses can devastate bird populations. 8.
Simian Virus 40 (SV40)contaminated money kidney cultures in
production of the Sabin poliovirus vaccine. Many feared it would cause cancer but it didnÕt. 9.
JC Virus causes Progressive multifocal leukoencephalopathy,
which is often found in AIDS patients and can be fatal in less than a year. 10.
It is only just newly discovered that Merkel Cell Polyomavirus
causes Merkel Cell Carcinoma, which is a lethal skin cancer. |
Polyomaviridae
on the Molecular Level
|
Type of Nucleic Acid: |
DNA |
|
Strandedness: |
Double stranded |
|
Genome morphology: |
Circular, supercoiled |
|
Genome Length: |
5 kilobases |
|
Virion type: |
Icosahedral |
|
Enveloped or naked: |
Naked (no envelope) |
|
Capsid Morphology: |
T = 7 ; quasiequivalence (pentons and hexons both pentameric) |
|
Proteins: |
VP1, VP2, VP3, Agno, large T, small t |
|
Replication: |
Genome replicated using host polymerase in the nucleus. Assembly
also occurs in the nucleus. |
|
Inactivation: |
Largely RESISTANT—can survive heat and formalin |
Molecular Biology and Replication
Polyomaviridae is a
double-stranded DNA circular virus.
The replication strategy is unique among viral families—it
transcribes from both DNA strands at different times! The early domain transcribed from one strand while the large
domain is transcribed from the other, with the origin of replication (called
Ori) at the junction between the two strands.
The
viral DNA goes to the nucleus where replication takes place. The first domain is transcribed halfway
around the circle and then cleaved off and differentially spliced to create
several mRNAs, generally called the T antigens, which have multiple functions
including DNA helicase activity, APTase, and Pol-alpha binding. These activities depend on whether the T
antigen is phosphorylated by an unknown kinase.
Large T antigen such as in SV40 can bind
to Rb, p53, p107, and p300 in the absence of the small t antigens which develop
later. Attachment to Rb, p107, and
p300 will create ÔGOÕ signals for cellular replication, while attachment to p53
will inhibit normal activity of slowing cellular replication, thus creating a transformed
cell, which can lead to cancer. This
has been well studied in the literature although there are currently no clear
answers to stop this process.
Late genes are regulated by the large T
antigens, which are transcribed from the opposite strand of DNA. There are 2-3 proteins, depending on
the viru, and they make up the protein coat of the virus. Finally, membrane vesicles transport
the virion to the cellular surface where the new viral particles are
released.
Polyomaviridae as
a Pathogen
|
Transmission: |
Direct contact |
|
Host range: |
Warm blooded vertebrates (humans, monkeys, cattle, rabbits,
rats, mice, hampsters, and several species of birds) |
|
Viruses causing HUMAN disease: |
JC Virus (John Cunningham) BK Virus KI Virus (Karolinska Institute) WU Virus (Washington University) MCV/MCPyV (Merkel
cell polyomavirus) |
|
Viruses causing ANIMAL disease: |
SV40 (simian vacuolating agent 40) in monkeys MuPyV (Murine polyoma virus) in mice Budgerigar fledgling disease virus in birds |
|
Oncogenic Potential: |
YES. It causes a multitude of tumors in hamsters and other
species. |
Polyomaviridae History and Timeline
In
1950, polyomavirus was first isolated by Ludvig Gross although Sarah Stewart
and Bernice Eddy also played a role.
Steward coined the name to mean ÔpolyÕ many and ÔomaÕ for cancers. It went under the umbrella of ÔpapovaviridaeÕ
along with the papillomaviridae genus and vacuolating agents. In 1953, the mouse polyomavirus was
first isolated, making it the first DNA tumor virus to grow in culture. From 1955-1960, people were exposed to
SV40, which causes cancer in monkeys, through the live Sabin poliovirus
vaccine, which was grown in monkey cells.
The vaccine was pulled from the market after this was discovered in
1960, and people continued to fear the oncogenic potential of SV40 although
nothing ever happened.
In the 60s, 70s and 80s, scientists
continued to discover new viruses— Simian Agent 12 in 1963 and BK and JC
viruses in 1971, Lyphotropic papovavirus in 1979, Budgeringar Fledgling Disease
Virus in 1986, Baboon polyomavirus in 1989, among others. In the late 1970s, people started
talking about the role of p53 interacting with polyomaviruses to explain their
oncogenic potential, and scientists still believe that inactivating this gene
will increase the oncogenic potential of a virus.
In 2000, the papovaviridae family split
into the papilloma and polyomaviridae families due to their many dissimilarities
, thus giving polyoma its very own family! The most recent additions to this new family are the KI Virus
and WU Virus in 2007 (see below) and the Merkel Cell Virus (MCV) in 2008.
Check out this interactive
historical timeline recounting the development of the Polyomaviridae family.
Recent Findings from 2007-2008:
á
MCPˆMCC: Merkel Cell Polyomavirus
the Cause for Merkel Cell Carcinoma
o
Published in Science in February of 2008, researchers at the University
of Pittsburgh Cancer Institute have discovered that a fatal form of skin
cancer, Merkel Cell Carcinoma (MCC), may be linked to a virus they have named
Merkel Cell Polyomavirus (MCP). They
have found the virus in over 80% of cases with Merkel Cell Carcinoma, although
one can still develop the cancer without have the virus. They will need to do more work to
investigate how the connection works, which may lead to future cancer
treatment.
o
Primary Source: Huichen Feng, Masahiro Shuda, Yuan Chang, Patrick
S. Moore. ÒClonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma.Ó
Science 22 February 2008: Vol. 319. no. 5866, pp. 1096 – 1100. http://www.sciencemag.org/cgi/content/abstract/1152586.
o
Summary Article: ÒKSHV Laboratory New Pathogen Discovery.Ó Kaposi's
Sarcoma-associated Herpesvirus Laboratory, University of Pittsburgh. 2008. http://www.kshv.pitt.edu/pathogen.html.
Image of Merkel Cell
Carcinoma skin biopsy with pathogenic effects. Public Domain.
á
A new virus for polyomaviridae!
o
The researchers at the Karolinska Institute in Sweden discovered a
new polyomavirus during a systematic screening of hundreds of nasopharyngeal
aspirates that was designed to find human pathogens. The virus is currently called the KI virus, named after the Karolinska
Institute.
o
Primary Source: Allander T, Andreasson K, Gupta S, et al (2007).
"Identification of a third human polyomavirus". J. Virol. 81 (8):
4130–6. http://jvi.asm.org/cgi/content/full/81/8/4130?view=long&pmid=17287263.
á
ANOTHER new virus for polyomaviridae!!
o
Researchers at Washington University The patients that had the WU
virus were hospitalized with pneumonia, bronchiolitis, and upper respiratory
tract infection.
o
Primary Source: Gaynor AM, Nissen MD, Whiley DM, et al (2007).
"Identification of a novel polyomavirus from patients with acute
respiratory tract infections". PLoS Pathog. 3 (5): e64.
doi:10.1371/journal.ppat.0030064. PMID 17480120. http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0030064.
o
Summary Article: Binh-Minh Le, Lee M. Demertzis, Guang Wu, Robert
J. Tibbets, Richard Buller, Max Q. Arens, Anne M. Gaynor, Gregory A. Storch,
and David Wang. ÒClinical and Epidemiologic Characterization of WU Polyomavirus
Infection.Ó St. Louis, Missouri. December 2007. http://www.cdc.gov/eid/content/13/12/1936.htm.
á
SV40 Crystallization Process on the Nuclear Level
o
On a biomolecular level, DNA replication occurs by having ÔinitiatorsÕ
bind to origins of replication. In
polyomaviridae, this occurs because there are four pentanucleotide binding
sites that the initiators can bind to. The following paper gives an in-depth
view of structural processes in replication in polyomaviridae.
o
Primary Source: Gretchen Meinke, Paul Phelan, Stephanie Moine, Elena
Bochkareva, Alexey Bochkarev, Peter A. Bullock, Andrew Bohm. ÒThe Crystal
Structure of the SV40 T-Antigen Origin Binding Domain in Complex with DNA.Ó PLoS
Biology Vol. 5, No. 2, e23 doi:10.1371/journal.pbio.0050023. http://biology.plosjournals.org/perlserv/plosonline/?request=get-document&doi=10.1371%2Fjournal.pbio.0050023.
á
Antivirals for the Treatment of Polyomavirus BK Replication
o
For the first time, scientists are studying antiviral drug
activity on polyomavirus replication.
They are trying to figure out how to avoid polyoma viral replication
associated with nephropathy in kidney-transplant recipients where the presence
of the virus can cause significant cytopathology leading to impaired renal
function. They studied cidofovir,
leflunomide, fluoroquinolones and intravenous immunoglobulins and although they
could not find any definitive correlations, they were able to make
recommendations for future research.
o
Source: Rinaldo, Christine Hanssen; Hirsch, Hans H. ÒAntivirals for the
treatment of polyomavirus BK replication.Ó Expert Review of Anti-Infective
Therapy. Volume 5, Number 1, February 2007 , pp. 105-115(11). http://www.ingentaconnect.com/content/ftd/eri/2007/00000005/00000001/art00012.
Virus websites
á
International Committee on
Taxonomy of Viruses Database (ICTVdB) – This gives up to date
information on polyomaviridae taxonomy and viruses listed under the family.
á
National Cancer Institute Information on
Merkel Cell Carcinoma – This website give excellent
information on the disease and current research that is being done.
á
Wikipedia's Polyomaviridae – Access
the information on polyomaviridae updated by the world population on a regular
basis.
á
Encylopedia Britannica's
Polyomaviridae – This website offers a clear, distinct definition of
polyomaviridae.
Humans and Viruses web pages from past students:
á
Polyomaviridae 2005 – This
site offers a review of relatively recent findings and information on the
replication cycle of the disease.
á
Polyomaviridae 2004 - This website
gives a good outline of Polyoma basic knowledge and impact on human disease.
á
Papovaviridae 2000 - This
delightful site offers good descriptions of drug profiles and individual
viruses.
á
Papovaviridae 1999 - Most of this
site's links no longer work, although you can access excellent papova poetry
and disease basics.
á
Papovaviridae 1998 - This website
was created before Papovaviridae split into Papillomaviridae and Polyomaviridae
and gives an overview of viruses and biology.
á
Learn about other virus families – Access a
network of great information on other virus families from more Humans and
Viruses students.
New LINKS!
- Interactive
Viral Website from Scripps College – Learn about the quasiequivalence
in polyomaviruses and others as well as many other facts on this
interactive website.
- Merkel
Cell Carcinoma Support Network – This is a nonprofit dedicated to giving people
accurate information on merkel cell carcinoma and referral centers.
- Protect
Your Parrot –
Polyomaviruses are considered to be one of the gravest dangers for caged
birds around the world. Learn
what you can do to protect the animals that you love.
- Thoughts on Avian Polyomavirus by Dr.
David Phalen – This site gives a scholarly perspective on the
development from the avian side of the viral family from faculty at Texas
A&M University.
- Personal Stories and Freedom Flights – This is a little goofy, but you
can read true anecdotal stories about how people have dealt with
polyomavirus in their birds.
Finally,
as a part of the course, we are required to create unique pathogen cards for
various viruses. Check out these cool information-packed pathogen
cards! Play
the game and make your own!
á
Allander T, Andreasson K, Gupta S, et al (2007).
"Identification of a third human polyomavirus". J. Virol. 81 (8):
4130–6. http://jvi.asm.org/cgi/content/full/81/8/4130?view=long&pmid=17287263.
á
Dilworth, Stephen M. ÒPolyoma virus middle T antigen and its role
in identifying cancer-related molecules.Ó Dec. 2002
http://www.nature.com/nrc/journal/v2/n12/full/nrc946.html.
á
Fields Virology Fifth Edition. Ed. Knipe, David & Peter
Howley. 2007. Pg. 2264.
á
ÒFreedom Flights.Ó Exotic Bird Sancuary and Education. 2007. http://www.freedomflightsparrotrescue.ca/Diseases.html.
á
Gaynor AM, Nissen MD, Whiley DM, et al (2007).
"Identification of a novel polyomavirus from patients with acute
respiratory tract infections". PLoS Pathog. 3 (5): e64.
doi:10.1371/journal.ppat.0030064. PMID 17480120. http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0030064.
á
ÒMerkel Cell Carinoma: Information for Patients and Their
Physicians.Ó Seattle Cancer Care Alliance. March 08. http://www.merkelcell.org/.
á
Phalen, David. ÒAVIAN POLYOMAVIRUS: MY THOUGHTS.Ó Department of
Large Animal Medicine and Surgery, Texas A&M University. Dec 1997. http://www.blackstone-aviaries.com/polyom.html.
á
ÒPolyomavirus.Ó
CDC Images Public Domain. 2008 <http://phil.cdc.gov/PHIL_Images/08301998/00006/B82-0338_lores.jpg>.
á
ÒPolyoma/Avian Polyoma Virus.Ó AvianWeb: Pet Bird Resources. 2007.
http://www.avianweb.com/polyoma.html.
á
Siegel, Robert. ÒWhy DonÕt you Papova and See me Sometime?Ó
Lecture 2/16/08. Stanford Universty.
á
Strauss & Strauss. Viruses and Human Disease. 2008 pg. 324.
á
Villarreal, Luis. ÒCommon Mechanisms of Transformation by Small
DNA Tumor Viruses.Ó Proceedings of the 1989 ICN-UCI International Conference on
Virology. Newport Beach CA. http://books.google.com/books?hl=en&lr=&id=UZO1w_KRtg4C&oi=fnd&pg=PA1&dq=polyoma+history&ots=OA-oY1ExEK&sig=r2JEpVs9LHmaYOwqWOg24oBY2Lo#PPA2,M1.
_________________________________________________________________
Created by Stacie
Vilendrer, Human Biology Õ08
Stanford
University Department of Human Biology
Questions and
Comments Can be sent to staciev@stanford.edu