Herpesviral Latency-Associated Transcript Gene Promotes Assembly of Heterochromatin on Viral Lytic-Gene Promoters in Latent Infection

Herpesviruses are large, double-stranded DNA viruses that replicate in the nucleus of host cells and rely on host transcriptional machinery for viral gene expression. Also, viral DNA was significantly less protected from micrococcal nuclease (MNase) digestion up to 6 h postinfection (hpi). Viral entry into the host cell depends upon interactions between an HSV-1 particle and cell surface receptors. Soon after ICP0 was identified as an activator of gene expression, ICP0-null mutant viruses were constructed (42, 48). Periodic reactivation of latent virus causes episodes of active disease characterized by epithelial lesions at the site of the original primary infection. Absorbed: Journals that are combined with another title. The yield of R8502 mutant virus in Vero, HEp-2, and human embryonic lung cells exposed to 0.1 pfu of virus per cell was 100-, 10-, and 10-fold higher, respectively, than those of R8501 mutant virus.

ATM (ataxia telangiectasia-mutated), ATR (ATM and Rad3-related) and DNA-PKcs (DNA-dependent protein kinase catalytic subunit) are phosphoinositide-3-kinase-related protein kinases (PIKKs) that are rapidly activated in response to different forms of genotoxic stress. In this study, we found genetic evidence that an HSV lytic protein is functional during latent infection, and this protein may provide a new target for antivirals that target both lytic and latent infections. Nuclear HSV-1 DNA did not fractionate as protein-free HSV-1 DNA but as DNA in cellular nucleosomes. The second specific aim is to investigate the roles of HSV-1 miRNAs that counteract innate immunity using viral mutants affected for these miRNAs, with emphasis on whether these miRNAs promote latency by abetting host survival in the face of HSV-1 infection. Links to PubMed are also available for Selected References. Interestingly, Stat3 knockout mice failed to expand the CD8+ conventional DC (cDC) population upon HSV-1 infection, and this was accompanied by impaired NK and CD8 T cell activation. Consequently, successful trans-complementation, which is determined by measuring de novo production of infectious viral progeny, indicates absence of dominant restrictions.

VP16 binds to the cis-regulatory sequences on viral IE gene promoters as part of a protein complex that also includes two host cell proteins, Oct-1 and HCF-1 (67). Mechanisms of regulation via H3K4me are well understood. 2004. Journal of Virology 14, 640-651. Author contributions: Q.-Y.W., D.M.C., and D.M.K. These results were supported by our findings that IE gene expression was not impaired in mutant cell lines that did not express functional coactivators. J.

Based on common control of a number of DNA viruses by epigenetic modulation, it was also demonstrated that this LSD1 inhibitor blocks initial gene expression of the human cytomegalovirus and adenovirus type 5. Periodic reactivation of latent virus causes episodes of active disease characterized by epithelial lesions at the site of the original primary infection. M., A. However, after viral DNA replication initiates, histones appear not to associate with newly synthesized viral genomes. Because HSV genomes begin as linear, double-stranded DNA during infection, host cells may treat the ends of incoming genomes as DNA double strand breaks (DSB) and subsequently repair these ends by circularization of genomes. Collectively, these results suggest that Egr-1 is efficiently induced upon HSV-1 lytic infection and may play a key role in the viral replication and the disease progression in eyes. Array analysis also mapped transcripts to three large intergenic regions previously thought to be transcriptionally silent, results subsequently confirmed by Northern blot and reverse transcription-PCR analysis.

These dynamics reconcile the weak interactions between HSV-1 genomes and chromatin proteins, detected by nuclease protection and chromatin immunoprecipitation, with the proposed regulation of HSV-1 gene expression by chromatin, supported by the marks in the chromatin in the viral genomes and the abilities of the HSV-1 transcription activators to modulate chromatin. However, available small-molecule LSD1 inhibitors are not originally designed to inhibit LSD1, but rather monoamine oxidases (MAO) in general. Further, inhibition of H3.3 association, via reduced expression of the H3.3 chaperone HIRA, significantly reduces the levels of HSV-1 mRNA. However, the chromatin modifications associated with transcribed and non-transcribed HSV-1 genes were those associated with active or repressed transcription, respectively. Interestingly, unimmunized mice were only susceptible to intravaginal (ivag) infection with HSV-2 during diestrus. PNU-183792, a 4-oxo-dihydroquinoline non-nucleoside inhibitor, is a broad-spectrum antiviral compound that has proven effective against many human and animal herpes viruses including HSV-1 (Brideau et al., 2002). Virol.

These changes lead to either a template for genome replication during the productive cycle or a persistent stable genome configuration during latency. Cellular processes requiring access to the DNA genome are regulated by an overlay of epigenetic modifications, including histone modification and chromatin remodeling. (2009) The histone variant H3.3 regulates gene expression during lytic infection by herpes HSV-1. However, the mechanisms that account for such low levels–how histone deposition on the viral genome is blocked or how histones are removed from the genome–are not yet defined. Ensuing DNA synthesis resulted in the generation of head-to-tail concatemers which were subsequently cleaved into monomeric units and packaged into the nascent viral capsid.

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