scholarly journals Herpes Simplex Virus 1 Strains 17syn+ and KOS(M) Differ Greatly in Their Ability To Reactivate from Human Neurons In Vitro

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
Tristan R. Grams ◽  
Terri G. Edwards ◽  
David C. Bloom
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Latent Infection ◽  
Neuronal Cell ◽  
Herpes Simplex Virus 1 ◽  
Viral Genomes ◽  
Human Neuronal Cell ◽  
Cell Line Model ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus 1 (HSV-1) establishes a lifelong latent infection in peripheral nerve ganglia. Periodically, the virus reactivates from this latent reservoir and is transported to the original site of infection. Strains of HSV-1 have been noted to vary greatly in their virulence and reactivation efficiencies in animal models. While HSV-1 strain 17syn+ can be readily reactivated, strain KOS(M) shows little to no reactivation in the mouse and rabbit models of induced reactivation. Additionally, 17syn+ is markedly more virulent in vivo than KOS. This has raised questions regarding potential strain-specific differences in neuroinvasion and neurovirulence and their contribution to differences in the establishment of latency (or ability to spread back to the periphery) and to the reactivation phenotype. To determine if any difference in the ability to reactivate between strains 17syn+ and KOS(M) is manifest at the level of neurons, we utilized a recently characterized human neuronal cell line model of HSV latency and reactivation (LUHMES). We found that KOS(M) established latency with a higher number of viral genomes than strain 17syn+. Strikingly, we show that the KOS(M) viral genomes have a higher burden of heterochromatin marks than strain 17syn+. The increased heterochromatin profile for KOS(M) correlates with the reduced expression of viral lytic transcripts during latency and impaired induced reactivation compared to that of 17syn+. These results suggest that genomes entering neurons from HSV-1 infections with strain KOS(M) are more prone to rapid heterochromatinization than those of 17syn+ and that this results in a reduced ability to reactivate from latency. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes a lifelong infection in neuronal cells. The virus periodically reactivates and causes recurrent disease. Strains of HSV-1 vary greatly in their virulence and potential to reactivate in animal models. Although these differences are phenotypically well defined, factors contributing to the strains’ abilities to reactivate are largely unknown. We utilized a human neuronal cell line model of HSV latency and reactivation (LUHMES) to characterize the latent infection of two HSV-1 wild-type strains. We find that strain-specific differences in reactivation are recapitulated in LUHMES. Additionally, these differences correlate with the degree of heterochromatinization of the latent genomes. Our data suggest that the epigenetic state of the viral genome is an important determinant of reactivation that varies in a strain-specific manner. This work also shows the first evidence of strain-specific differences in reactivation outside the context of the whole animal at a human neuronal cell level.

scholarly journals A Herpes Simplex Virus 1 (McKrae) Mutant Lacking the Glycoprotein K Gene Is Unable To Infect via Neuronal Axons and Egress from Neuronal Cell Bodies

mBio ◽  
2012 ◽  
Vol 3 (4) ◽  
Author(s):  
Andrew T. David ◽  
Ahmad Saied ◽  
Anu Charles ◽  
Ramesh Subramanian ◽  
Vladimir N. Chouljenko ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Recombinant Virus ◽  
Neuronal Cell ◽  
Viral Envelope ◽  
Viral Glycoprotein ◽  
Herpes Simplex Virus 1 ◽  
Neuronal Cell Bodies ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTWe have shown that the herpes simplex virus 1 (HSV-1) gK gene is essential for efficient replication and spread in the corneal epithelium and trigeminal ganglion neuroinvasion in mice (A. T. David, A. Baghian, T. P. Foster, V. N. Chouljenko, and K. G. Kousoulas, Curr. Eye Res. 33:455–467, 2008). To further investigate the role of gK in neuronal infection, we utilized a microfluidic chamber system separating neuronal cell bodies and axonal termini. HSV-1 (McKrae) engineered virus constitutively expressing enhanced green fluorescence protein (GFP) was efficiently transmitted in both a retrograde and an anterograde manner. These results were corroborated by expression of virion structural proteins in either chamber, as well as detection of viral genomes and infectious viruses. In contrast, efficient infection of either chamber with a gK-null virus did not result in infection of the apposed chamber. These results show that gK is an important determinant in virion axonal infection. Moreover, the inability of the gK-null virus to be transmitted in an anterograde manner suggests that virions acquire cytoplasmic envelopes prior to entering axons.IMPORTANCEHerpes simplex virus 1 (HSV-1) enters mucosal epithelial cells and neurons via fusion of the viral envelope with cellular membranes, mediated by viral glycoprotein B (gB) in cooperation with other viral glycoproteins. Retrograde transport of virions to neuronal cell bodies (somata) establishes lifelong latent infection in ganglionic neurons. We have previously reported that gK binds gB and is required for gB-mediated membrane fusion (Jambunatathan et al., J. Virol. 85:12910–12918, 2011; V. N. Chouljenko, A. V. Iyer, S. Chowdhury, J. Kim, and K. G. Kousoulas, J. Virol. 84:8596–8606, 2010). In the current study, we constructed a recombinant virus with the gK gene deleted in the highly virulent ocular HSV-1 strain McKrae. This recombinant virus failed to infect rat ganglionic neuronal axons alone or cocultured with Vero cells in microfluidic chambers. In addition, lack of gK expression prevented anterograde transmission of virions. These results suggest that gK is a critical determinant for neuronal infection and transmission.

scholarly journals Herpes Simplex Virus 1 Lytic Infection Blocks MicroRNA (miRNA) Biogenesis at the Stage of Nuclear Export of Pre-miRNAs

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Dongli Pan ◽  
Gang Li ◽  
Jenna Morris-Love ◽  
Shuyuan Qi ◽  
Lei Feng ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Nuclear Export ◽  
Latent Infection ◽  
Mature Mirnas ◽  
Lytic Infection ◽  
Mirna Biogenesis ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) switches between two infection programs, productive (“lytic”) and latent infection. Some HSV-1 microRNAs (miRNAs) have been hypothesized to help control this switch, and yet little is known about regulation of their expression. Using Northern blot analyses, we found that, despite inherent differences in biogenesis efficiency among six HSV-1 miRNAs, all six exhibited high pre-miRNA/miRNA ratios during lytic infection of different cell lines and, when detectable, in acutely infected mouse trigeminal ganglia. In contrast, considerably lower ratios were observed in latently infected ganglia and in cells transduced with lentiviral vectors expressing the miRNAs, suggesting that HSV-1 lytic infection blocks miRNA biogenesis. This phenomenon is not specific to viral miRNAs, as a host miRNA expressed from recombinant HSV-1 also exhibited high pre-miRNA/miRNA ratios late during lytic infection. The levels of most of the mature miRNAs remained stable during infection in the presence of actinomycin D, indicating that the high ratios are due to inefficient pre-miRNA conversion to miRNA. Cellular fractionation experiments showed that late (but not early) during infection, pre-miRNAs were enriched in the nucleus and depleted in the cytoplasm, indicating that nuclear export was blocked. A mutation eliminating ICP27 expression or addition of acyclovir reduced pre-miRNA/miRNA ratios, but mutations drastically reducing Us11 expression did not. Thus, HSV-1 lytic infection inhibits miRNA biogenesis at the step of nuclear export and does so in an ICP27- and viral DNA synthesis-dependent manner. This mechanism may benefit the virus by reducing expression of repressive miRNAs during lytic infection while permitting elevated expression during latency.IMPORTANCEVarious mechanisms have been identified by which viruses target host small RNA biogenesis pathways to achieve optimal infection outcomes. Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen whose successful persistence in the host entails both productive (“lytic”) and latent infection. Although many HSV-1 miRNAs have been discovered and some are thought to help control the lytic/latent switch, little is known about regulation of their biogenesis. By characterizing expression of both pre-miRNAs and mature miRNAs under various conditions, this study revealed striking differences in miRNA biogenesis between lytic and latent infection and uncovered a regulatory mechanism that blocks pre-miRNA nuclear export and is dependent on viral protein ICP27 and viral DNA synthesis. This mechanism represents a new virus-host interaction that could limit the repressive effects of HSV-1 miRNAs hypothesized to promote latency and may shed light on the regulation of miRNA nuclear export, which has been relatively unexplored.

scholarly journals CCCTC-Binding Factor Acts as a Heterochromatin Barrier on Herpes Simplex Viral Latent Chromatin and Contributes to Poised Latent Infection

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Jennifer S. Lee ◽  
Priya Raja ◽  
Dongli Pan ◽  
Jean M. Pesola ◽  
Donald M. Coen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Binding Sites ◽  
Latent Infection ◽  
Ctcf Binding ◽  
Herpes Simplex Virus 1 ◽  
Binding Factor ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) establishes latent infection in neurons via a variety of epigenetic mechanisms that silence its genome. The cellular CCCTC-binding factor (CTCF) functions as a mediator of transcriptional control and chromatin organization and has binding sites in the HSV-1 genome. We constructed an HSV-1 deletion mutant that lacked a pair of CTCF-binding sites (CTRL2) within the latency-associated transcript (LAT) coding sequences and found that loss of these CTCF-binding sites did not alter lytic replication or levels of establishment of latent infection, but their deletion reduced the ability of the virus to reactivate from latent infection. We also observed increased heterochromatin modifications on viral chromatin over theLATpromoter and intron. We therefore propose that CTCF binding at theCTRL2sites acts as a chromatin insulator to keep viral chromatin in a form that is poised for reactivation, a state which we call poised latency.IMPORTANCEHerpes simplex virus 1 (HSV-1) is a human pathogen that persists for the lifetime of the host as a result of its ability to establish latent infection within sensory neurons. The mechanism by which HSV-1 transitions from the lytic to latent infection program is largely unknown; however, HSV-1 is able to coopt cellular silencing mechanisms to facilitate the suppression of lytic gene expression. Here, we demonstrate that the cellular CCCTC-binding factor (CTCF)-binding site within the latency associated transcript (LAT) region is critical for the maintenance of a specific local chromatin structure. Additionally, loss of CTCF binding has detrimental effects on the ability to reactivate from latent infection. These results argue that CTCF plays a critical role in epigenetic regulation of viral gene expression to establish and/or maintain a form of latent infection that can reactivate efficiently.

scholarly journals The CCCTC Binding Factor, CTRL2, Modulates Heterochromatin Deposition and the Establishment of Herpes Simplex Virus 1 Latency In Vivo

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Shannan D. Washington ◽  
Pankaj Singh ◽  
Richard N. Johns ◽  
Terri G. Edwards ◽  
Michael Mariani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Transcriptional Control ◽  
Neuronal Cell ◽  
Ocular Infection ◽  
Herpes Simplex Virus 1 ◽  
Lytic Gene ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The cellular insulator protein CTCF plays a role in herpes simplex virus 1 (HSV-1) latency through the establishment and regulation of chromatin boundaries. We previously found that the CTRL2 regulatory element downstream from the latency-associated transcript (LAT) enhancer was bound by CTCF during latency and underwent CTCF eviction at early times postreactivation in mice latently infected with 17syn+ virus. We also showed that CTRL2 was a functional enhancer-blocking insulator in both epithelial and neuronal cell lines. We hypothesized that CTRL2 played a direct role in silencing lytic gene expression during the establishment of HSV-1 latency. To test this hypothesis, we used a recombinant virus with a 135-bp deletion spanning only the core CTRL2 insulator domain (ΔCTRL2) in the 17syn+ background. Deletion of CTRL2 resulted in restricted viral replication in epithelial cells but not neuronal cells. Following ocular infection, mouse survival decreased in the ΔCTRL2-infected cohort, and we found a significant decrease in the number of viral genomes in mouse trigeminal ganglia (TG) infected with ΔCTRL2, indicating that the CTRL2 insulator was required for the efficient establishment of latency. Immediate early (IE) gene expression significantly increased in the number of ganglia infected with ΔCTRL2 by 31 days postinfection relative to the level with 17syn+ infection, indicating that deletion of the CTRL2 insulator disrupted the organization of chromatin domains during HSV-1 latency. Finally, chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) analyses of TG from ΔCTRL2-infected mice confirmed that the distribution of the repressive H3K27me3 (histone H3 trimethylated at K27) mark on the ΔCTRL2 recombinant genomes was altered compared to that of the wild type, indicating that the CTRL2 site modulates the repression of IE genes during latency. IMPORTANCE It is becoming increasingly clear that chromatin insulators play a key role in the transcriptional control of DNA viruses. The gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) utilize chromatin insulators to order protein recruitment and dictate the formation of three-dimensional DNA loops that spatially control transcription and latency. The contribution of chromatin insulators in alphaherpesvirus transcriptional control is less well understood. The work presented here begins to bridge that gap in knowledge by showing how one insulator site in HSV-1 modulates lytic gene transcription and heterochromatin deposition as the HSV-1 genome establishes latency.

scholarly journals SAMHD1 Restricts Herpes Simplex Virus 1 in Macrophages by Limiting DNA Replication

2013 ◽  
Vol 87 (23) ◽  
pp. 12949-12956 ◽  
Author(s):  
Eui Tae Kim ◽  
Tommy E. White ◽  
Alberto Brandariz-Núñez ◽  
Felipe Diaz-Griffero ◽  
Matthew D. Weitzman
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Reverse Transcription ◽  
Immune Defense ◽  
Herpes Simplex Virus 1 ◽  
Viral Genomes ◽  
Viral Spread ◽  
Intracellular Dntp ◽  
Simplex Virus ◽  
Hsv 1

Macrophages play important roles in host immune defense against virus infection. During infection by herpes simplex virus 1 (HSV-1), macrophages acquire enhanced antiviral potential. Restriction of HSV-1 replication and progeny production is important to prevent viral spread, but the cellular mechanisms that inhibit the DNA virus in macrophages are unknown. SAMHD1 was recently identified as a retrovirus restriction factor highly expressed in macrophages. The SAMHD1 protein is expressed in both undifferentiated monocytes and differentiated macrophages, but retroviral restriction is limited to differentiated cells by modulation of SAMHD1 phosphorylation. It is proposed to block reverse transcription of retroviral RNA into DNA by depleting cellular deoxynucleotide triphosphates (dNTPs). Viruses with DNA genomes do not employ reverse transcription during infection, but replication of their viral genomes is also dependent on intracellular dNTP concentrations. Here, we demonstrate that SAMHD1 restricts replication of the HSV-1 DNA genome in differentiated macrophage cell lines. Depleting SAMHD1 in THP-1 cells enhanced HSV-1 replication, while ectopic overexpression of SAMHD1 in U937 cells repressed HSV-1 replication. SAMHD1 did not impact viral gene expression from incoming HSV-1 viral genomes. HSV-1 restriction involved the dNTP triphosphohydrolase activity of SAMHD1 and was partially overcome by addition of exogenous deoxynucleosides. Unlike retroviruses, restriction of HSV-1 was not affected by SAMHD1 phosphorylation status. Our results suggest that SAMHD1 functions broadly to inhibit replication of DNA viruses in nondividing macrophages.

scholarly journals Attenuated Herpes Simplex Virus 1 (HSV-1) Expressing a Mutant Form of ICP6 Stimulates a Strong Immune Response That Protects Mice against HSV-1-Induced Corneal Disease

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
David J. Davido ◽  
Eleain M. Tu ◽  
Hong Wang ◽  
Maria Korom ◽  
Andreu Gazquez Casals ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Latent Infection ◽  
Prophylactic Vaccine ◽  
Null Mutant ◽  
Herpes Simplex Virus 1 ◽  
Corneal Disease ◽  
Challenge Virus ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTWe previously isolated a herpes simplex virus 1 (HSV-1) mutant, KOS-NA, that carries two nonsynonymous mutations inUL39, resulting in L393P and R950H amino acid substitutions in infected cell protein 6 (ICP6). Our published data studying KOS-NA pathogenesis strongly suggest that one of these ICP6 substitutions expressed from KOS-NA, R950H, severely impaired acute viral replication in the eyes and trigeminal ganglia of mice after inoculation onto the cornea and consequently impaired establishment and reactivation from latency. Because of its significant neuroattenuation, we tested KOS-NA as a potential prophylactic vaccine against HSV-1 in a mouse model of corneal infection. KOS-NA stimulated stronger antibody and T cell responses than a replication-competent ICP0-null mutant and a replication-incompetent ICP8-null mutant optimized for immunogenicity. Immunizations with the ICP0−, ICP8−, and KOS-NA viruses all reduced replication of wild-type HSV-1 challenge virus in the corneal epithelium to similar extents. Low immunizing doses of KOS-NA and the ICP8−virus, but not the ICP0−virus, protected mice against eyelid disease (blepharitis). Notably, only KOS-NA protected almost completely against corneal disease (keratitis) and greatly reduced latent infection by challenge virus. Thus, vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated disease of the eye, even at a very low immunizing dose. These results suggest that KOS-NA may be the foundation of an effective prophylactic vaccine to prevent or limit HSV-1 ocular diseases.IMPORTANCEHSV-1 is a ubiquitous human pathogen that infects the majority of the world's population. Although most infections are asymptomatic, HSV-1 establishes lifelong latency in infected sensory neurons, from which it can reactivate to cause deadly encephalitis or potentially blinding eye disease. No clinically effective vaccine is available. In this study, we tested the protective potential of a neuroattenuated HSV-1 mutant (KOS-NA) as a vaccine in mice. We compared the effects of immunization with KOS-NA to those of two other attenuated viruses, a replication-competent (ICP0−) virus and a replication-incompetent (ICP8−) virus. Our data show that KOS-NA proved superior to the ICP0- and ICP8-null mutants in protecting mice from corneal disease and latent infection. With its significant neuroattenuation, severe impairment in establishing latency, and excellent protective effect, KOS-NA represents a significant discovery in the field of HSV-1 vaccine development.

scholarly journals Inhibitors of Nucleotidyltransferase Superfamily Enzymes Suppress Herpes Simplex Virus Replication

2014 ◽  
Vol 58 (12) ◽  
pp. 7451-7461 ◽  
Author(s):  
John E. Tavis ◽  
Hong Wang ◽  
Ann E. Tollefson ◽  
Baoling Ying ◽  
Maria Korom ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Dna Replication ◽  
Herpes Simplex ◽  
Enzyme Inhibitors ◽  
Herpes Simplex Virus 1 ◽  
Dna Viruses ◽  
Viral Genomes ◽  
Multiple Processes ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpesviruses are large double-stranded DNA viruses that cause serious human diseases. Herpesvirus DNA replication depends on multiple processes typically catalyzed by nucleotidyltransferase superfamily (NTS) enzymes. Therefore, we investigated whether inhibitors of NTS enzymes would suppress replication of herpes simplex virus 1 (HSV-1) and HSV-2. Eight of 42 NTS inhibitors suppressed HSV-1 and/or HSV-2 replication by >10-fold at 5 μM, with suppression at 50 μM reaching ∼1 million-fold. Five compounds in two chemical families inhibited HSV replication in Vero and human foreskin fibroblast cells as well as the approved drug acyclovir did. The compounds had 50% effective concentration values as low as 0.22 μM with negligible cytotoxicity in the assays employed. The inhibitors suppressed accumulation of viral genomes and infectious particles and blocked events in the viral replication cycle before and during viral DNA replication. Acyclovir-resistant mutants of HSV-1 and HSV-2 remained highly sensitive to the NTS inhibitors. Five of six NTS inhibitors of the HSVs also blocked replication of another herpesvirus pathogen, human cytomegalovirus. Therefore, NTS enzyme inhibitors are promising candidates for new herpesvirus treatments that may have broad efficacy against members of the herpesvirus family.

scholarly journals Histone deacetylase inhibitors reduce the number of herpes simplex virus-1 genomes initiating expression in individual cells

2016 ◽  
Author(s):  
Shapira Lev ◽  
Ralph Maya ◽  
Tomer Enosh ◽  
Cohen Shai ◽  
Kobiler Oren
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Types ◽  
Nuclear Bodies ◽  
Host Proteins ◽  
Herpes Simplex Virus 1 ◽  
Viral Genomes ◽  
Early Protein ◽  
Simplex Virus ◽  
Hsv 1

AbstractAlthough many viral particles can enter a single cell, the number of viral genomes per cell that establish infection is limited. However, mechanisms underlying this restriction were not explored in depth. For herpesviruses, one of the possible mechanisms suggested is chromatinization and silencing of the incoming genomes. To test this hypothesis, we followed infection with three herpes simplex virus 1 (HSV-1) fluorescence-expressing recombinants in the presence or absence of histone deacetylases inhibitors (HDACi’s). Unexpectedly, a lower number of viral genomes initiated expression in the presence of these inhibitors. This phenomenon was observed using several HDACi: Trichostatin A (TSA), Suberohydroxamic Acid (SBX), Valporic Acid (VPA) and Suberoylanilide Hydoxamic Acid (SAHA). We found that HDACi presence did not change the progeny outcome from the infected cells but did alter the kinetic of the infection. Different cell types (HFF, Vero and U2OS), which vary in their capability to activate intrinsic and innate immunity, show a cell specific basal average number of viral genomes establishing infection. Importantly, in all cell types, treatment with TSA reduced the number of viral genomes. ND10 nuclear bodies are known to interact with the incoming herpes genomes and repress viral replication. The viral immediate early protein, ICP0, is known to disassemble the ND10 bodies and to induce degradation of some of the host proteins in these domains. HDACi treated cells expressed higher levels of some of the host ND10 proteins (PML and ATRX), which may down regulate the number of viral genomes initiating expression per cell. Corroborating this hypothesis, infection with three HSV-1 recombinants carrying a deletion in the gene coding for ICP0, show a reduction in the number of genomes being expressed in U2OS cells. We suggest that alterations in the levels of host proteins involved in intrinsic antiviral defense may result in differences in the number of genomes that initiate expression.

Assembly of VP26 in herpes simplex virus-1 capsid implicated by 3-D structure of recombinant capsid

1995 ◽  
Vol 53 ◽  
pp. 840-841
Author(s):  
Z. Hong Zhou ◽  
Jing He ◽  
Joanita Jakana ◽  
J. D. Tatman ◽  
Frazer J. Rixon ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
3D Structure ◽  
Structure Study ◽  
Herpes Simplex Virus 1 ◽  
Shell Proteins ◽  
Life Threatening ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus which is implicated in diseases ranging from self-curing cold sores to life-threatening infections. The 2500 Å diameter herpes virion is composed of a glycoprotein spike containing, lipid envelope, enclosing a protein layer (the tegument) in which is embedded the capsid (which contains the dsDNA genome). The B-, and A- and C-capsids, representing different morphogenetic stages in HSV-1 infected cells, are composed of 7, and 5 structural proteins respectively. The three capsid types are organized in similar T=16 icosahedral shells with 12 pentons, 150 hexons, and 320 connecting triplexes. Our previous 3D structure study at 26 Å revealed domain features of all these structural components and suggested probable locations for the outer shell proteins, VP5, VP26, VP19c and VP23. VP5 makes up most of both pentons and hexons. VP26 appeared to bind to the VP5 subunit in hexon but not to that in penton.

scholarly journals Herpes simplex virus 1 targets IRF7 via ICP0 to limit type I IFN induction

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
David Shahnazaryan ◽  
Rana Khalil ◽  
Claire Wynne ◽  
Caroline A. Jefferies ◽  
Joan Ní Gabhann-Dromgoole ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Tear Film ◽  
Cell Protein ◽  
Type I ◽  
Type I Ifn ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

AbstractHerpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi-pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti-viral and pro-inflammatory cytokines. However, given that HSV-1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual’s lifetime, there is significant interest in understanding the mechanisms employed by HSV-1 to downregulate the anti-viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target.

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