Abstract
BackgroundHuman polyomavirus JC (JCV) is the etiologic agent of a brain disease, known as progressive multifocal leukoencephalopathy (PML). The JCV genome encodes a small multifunctional phospho-protein, agnoprotein, from the late coding region of the virus, whose regulatory functions in viral replication cycle remain elusive. In this work, the functional role of JCV and SV40 agnoproteins in virion release was investigated using a point mutant (Pt) of each virus, where the ATG codon of agnoprotein was mutated to abrogate its expression.ResultsAnalysis of both viral protein expression and replication using Pt mutant of each virus revealed that both processes were substantially down-regulated in the absence of agnoprotein compared to wild-type (WT) virus. Complementation studies in cells, which are constitutively expressing JCV agnoprotein and transfected with the JCV Pt mutant genome, showed an elevation in the level of viral DNA replication near to that observed for WT. Constitutive expression of large T antigen was found to be not sufficient to compensate the loss of agnoprotein for efficient replication of neither JCV nor SV40 in vivo. Examination of the viral release process for both JCV and SV40 Pt mutants showed that viral particles are efficiently released from the infected cells in the absence of agnoprotein but were found to be mostly deficient in viral DNA content.ConclusionsThe results of this study provide evidence that agnoprotein plays an important role in the polyomavirus JC and SV40 life cycle. Infection by agnoprotein-negative mutants of both viruses results in the release of virions that are mostly deficient in DNA content.
Highlights
Human polyomavirus JC (JCV) is the etiologic agent of a brain disease, known as progressive multifocal leukoencephalopathy (PML)
We provide experimental evidence indicating that both JCV and simian virus 40 (SV40) virions are efficiently released from the infected cells in the absence of agnoprotein, the released viral particles are mostly deficient in DNA content, which greatly hampers the ability of the propagation of the mutant virus relative to wild-type
We investigated whether JCV and SV40 agnoproteins play regulatory roles in release of virions from infected cells, utilizing agnoprotein point mutants of each virus
Summary
Human polyomavirus JC (JCV) is the etiologic agent of a brain disease, known as progressive multifocal leukoencephalopathy (PML). A large number of studies indicate that the small regulatory proteins of many viruses play important roles in various aspects of viral infection cycle, including replication [1,2,3], transcription [4,5,6,7,8,9,10], translation [11], export of viral transcripts from nucleus to cytoplasm [12], viral assembly [13] and release of viral particles [14,15] These proteins may modulate host-cell functions by deregulating the expression of key cellular genes [16]. While the amino-terminal and central regions of each agnoprotein exhibit considerable sequence identity with one another, sequences toward the carboxy-terminal region are more divergent
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