polyomavirus

Introduction

small, nonenveloped DNA virus

three capsid proteinsVP1,VP2 and VP3
double-stranded covalently closed circular DNA
5kbp genome length
icosahedral symmetry
relative resistant to heat formalin and lipid solvent
only VP1 exposed on surface of capsid

Introduction
They are potentially oncogenic (tumorcausing)
They often persist as latent infections in a
host without causing disease, but may
produce tumors in a host of a different
species, or a host with an ineffective
immune system.
The name polyoma refers to the viruses'
ability to produce multiple (poly-) tumors (oma).

HISTORY
Research dates to the 1950s
Murine leukemia virus passagedthrough mice,
developed salivary glandtumors and not
leukemia
Next member Simian virus 40 (SV40), 1960
1971, human polyomaviruses from
immunocompromised patients
JC , brain from patient with PML
BK from Urine

Classification
ICTV recommended dividing the
family of Polyomaviridae into three
genera:
Genus Orthopolyomavirus (SV40)
Genus Wukipolyomavirus (KI
polyomavirus)
Genus Avipolyomavirus (Avian
polyomavirus)

Genome
The genome is circular composed of
double stranded DNA
and has six genes:
large T, small t,
viral protein 1 (VP1),
viral protein 2 (VP2),
viral protein 3 (VP3)
agnoprotein.

Genome Structure
Genome divided in 3 parts
early region - expressed before onset of
replication
late region - expressed after replication
regulatory region - origin of replication,
promoters for early and late transcription
non overlapping late/early ,transcribed from
opposite strand
large T antigen binds to tumor suppressor
proteins Rb and p53,initiate cell cycle

Replication
attachment
(sialic acid)
entry
uncoating
Early gene expression
Late gene expression
Release

Early gene expression

Responsible for the synthesis of non-structural proteins
role of the non-structural proteins is to regulate the
cellular mechanisms Close to the N terminal end of
polyomavirus genome are enhancer elements which
induce activation and transcription of a molecule known
as the T-antigen
Early mRNAs, encoding T-antigen are produced by host
RNA polymerase II
T-antigen auto regulates early mRNAs, subsequently
leading to elevated levels of T-antigen
At high concentrations of T-antigen, early gene
expression is repressed, triggering the late phase of viral
infection to begin

Conti..
Genome replication acts to separate the
early and late phase gene expression. The
duplicated viral genome is synthesised
and processed as if it were cellular DNA,
exploiting the hosts machinery.
As the daughter viral DNA are synthesised
they associate with cellular nucleosomes
to form structures that are often referred
to as "minichromosomes". In this manner
the DNA is packaged more efficiently

Late gene expression

synthesizes the structural proteins

Responsible for the viral particle composition
This occurs during and after genome replication
As with the early gene expression products, late
gene expression generates an array of proteins as
a result of alternative splicing
Within each viral protein are 'nuclear localization
signals' which cause the viral proteins to amass in
the nucleus
Assembly of new virus particles consequently
occurs within the nucleus of the host cell

Large T-Antigens
large T-antigen plays a key role in regulating the viral life cycle
They bind to the viral origin of DNA replication and promotes
DNA synthesis
large T-antigen also modulates cellular signaling pathways by
binding to a number of cellular control proteins
This is achieved by a two prong attack of inhibiting tumor
suppressing genes
p53
retinoblastoma (RB)
ATPase-helicase, DNA polymerase association, and binding of
transcription preinitiation complex factors.
This abnormal stimulation of the cell cycle is a powerful force
for oncogenic transformation

Viral genetics

Small T-Antigens
Small T-antigen activates several cellular
pathways that stimulate cell proliferation
These commonly target protein
phosphatase 2A (PP2A)
Merkel cell polyomavirus small T antigen
encodes a unique domain, called the LTstabilization domain (LSD)
This binds to and inhibits the FBXW7 E3
ligase regulating both cellular and viral
oncoproteins

Agnoprotein
The agnoprotein is a small
multifunctional phospho-protein
found in the late coding part of the
genome
It appears to be involved in DNA
replication but the exact mechanism
remains unclear

Hosts

Diseases
Progressive Multifocal
Leukoencephalopathy(PML)
Haemorhagic Cystitis (post HSCT)
BK Nephropathy or Polyomavirusassociated nephropathy (PVAN)
rare, encephalitis, pneumonitis,
retinitis andvasculopathies

Pathogenesis