scholarly journals Evasion of Cytosolic DNA-Stimulated Innate Immune Responses by Herpes Simplex Virus 1

2018 ◽  
Vol 92 (6) ◽  
Author(s):  
Chunfu Zheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Innate Immune Responses ◽  
Herpes Simplex Virus 1 ◽  
Antiviral Responses ◽  
Cellular Dna ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Recognition of virus-derived nucleic acids by host pattern recognition receptors (PRRs) is crucial for early defense against viral infections. Recent studies revealed that PRRs also include several newly identified DNA sensors, most of which could activate the downstream adaptor stimulator of interferon genes (STING) and lead to the production of host antiviral factors. Herpes simplex virus 1 (HSV-1) is extremely successful in establishing effective infections, due to its capacity to counteract host innate antiviral responses. In this Gem, I summarize the most recent findings on the molecular mechanisms utilized by HSV-1 to target different steps of the cellular DNA-sensor-mediated antiviral signal pathway.

scholarly journals The Solute Carrier Transporter SLC15A3 Participates in Antiviral Innate Immune Responses against Herpes Simplex Virus-1

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Longzhen He ◽  
Baocheng Wang ◽  
Yuanyuan Li ◽  
Leqing Zhu ◽  
Peiling Li ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Innate Immune Responses ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

scholarly journals Gene expression profiling of monocytes displaying herpes simplex virus 1 induced dysregulation of antifungal defences

2009 ◽  
Vol 58 (10) ◽  
pp. 1283-1290 ◽  
Author(s):  
Claudio Cermelli ◽  
Carlotta Francesca Orsi ◽  
Alessandro Cuoghi ◽  
Andrea Ardizzoni ◽  
Enrico Tagliafico ◽  
...  
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Functional Data ◽  
Macrophage Activation ◽  
Molecular Mechanisms ◽  
Herpes Simplex Virus 1 ◽  
Fungal Adhesion ◽  
Simplex Virus ◽  
Hsv 1

Recently, we showed that herpes simplex virus 1 (HSV-1)-infected monocytes have altered antifungal defences, in particular they show augmented phagocytosis of Candida albicans followed by a failure of the intracellular killing of the ingested fungi. On the basis of these functional data, comparative studies were carried out on the gene expression profile of cells infected with HSV-1 and/or C. albicans in order to investigate the molecular mechanisms underlying such virus-induced dysfunction. Affymetrix GeneChip technology was used to evaluate the cell transcription pattern, focusing on genes involved in phagocytosis, fungal adhesion, antimicrobial activity and apoptosis. The results indicated there was: (a) prevalent inhibition of opsonin-mediated phagocytosis, (b) upregulation of several pathways of antibody- and complement-independent phagocytosis, (c) inhibition of macrophage activation, (d) marked dysregulation of oxidative burst, (e) induction of apoptosis.

scholarly journals The ESCRT-Related ATPase Vps4 Is Modulated by Interferon during Herpes Simplex Virus 1 Infection

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Jorge Ruben Cabrera ◽  
Richard Manivanh ◽  
Brian J. North ◽  
David A. Leib
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infections ◽  
Cell Types ◽  
Primary Neurons ◽  
Herpes Simplex Virus 1 ◽  
Escrt Machinery ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTInterferons (IFNs) and autophagy are critical neuronal defenses against viral infection. IFNs alter neuronal autophagy by promoting the accumulation of IFN-dependent LC3-decorated autophagic structures, termed LC3 clusters. Here, we analyzed LC3 clusters in sensory ganglia following herpes simplex virus 1 (HSV-1) infection. In the vicinity of acutely infected neurons, antigen-negative neurons contained structures resembling accumulated autophagosomes and autolysosomes that culminated in LC3 clusters. This accumulation reflects a delayed completion of autophagy. Theendosomalsortingcomplexesrequired fortransport (ESCRT) machinery participates in autophagosome closure and is also required for HSV-1 replication. In this study, our results showed that HSV-1 infectionin vivoand in primary neurons caused a decrease in Vps4 (a key ESCRT pathway ATPase) RNA and protein with concomitant Stat1 activation and LC3 cluster induction. We also observed that IFNs were sufficient to decrease RNA and protein levels of Vps4 in primary neurons and in other cell types. The accumulation of ubiquitin was also observed at the LC3 cluster sites. Together, our results show that IFNs modulate the ESCRT machinery in neurons in response to HSV-1 infections.IMPORTANCENeurons rely on IFNs and autophagy as major defenses against viral infections, and HSV must overcome such defenses in order to replicate. In addition to controlling host immunity, HSV must also control host membranes in order to complete its life cycle. HSV uses the host ESCRT membrane scission machinery for viral production and transport. Here we present evidence of a new IFN-dependent mechanism used by the host to prevent ESCRT subversion by HSV. This activity also impacts the dynamics of autophagy, possibly explaining the presence of recently described LC3 clusters in the HSV-infected nervous system. The induced accumulations of ubiquitin observed in these LC3 clusters resembled those observed in certain neurodegenerative diseases, suggesting possible mechanistic parallels between these conditions.

scholarly journals Herpes Simplex Virus 1 Deregulation of Host MicroRNAs

2018 ◽  
Vol 4 (4) ◽  
pp. 36 ◽  
Author(s):  
Maja Cokarić Brdovčak ◽  
Andreja Zubković ◽  
Igor Jurak
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Replication ◽  
Molecular Mechanisms ◽  
Gene Repression ◽  
Productive Infection ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

Viruses utilize microRNAs (miRNAs) in a vast variety of possible interactions and mechanisms, apparently far beyond the classical understanding of gene repression in humans. Likewise, herpes simplex virus 1 (HSV-1) expresses numerous miRNAs and deregulates the expression of host miRNAs. Several HSV-1 miRNAs are abundantly expressed in latency, some of which are encoded antisense to transcripts of important productive infection genes, indicating their roles in repressing the productive cycle and/or in maintenance/reactivation from latency. In addition, HSV-1 also exploits host miRNAs to advance its replication or repress its genes to facilitate latency. Here, we discuss what is known about the functional interplay between HSV-1 and the host miRNA machinery, potential targets, and the molecular mechanisms leading to an efficient virus replication and spread.

scholarly journals Disassembly of the TRIM23-TBK1 Complex by the Us11 Protein of Herpes Simplex Virus 1 Impairs Autophagy

2019 ◽  
Vol 93 (17) ◽  
Author(s):  
Xing Liu ◽  
Rachel Matrenec ◽  
Michaela U. Gack ◽  
Bin He
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Molecular Mechanisms ◽  
Host Cells ◽  
Viral Escape ◽  
Wild Type Virus ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Us11 Protein ◽  
Hsv 1

ABSTRACTThe Us11 protein encoded by herpes simplex virus 1 (HSV-1) functions to impair autophagy; however, the molecular mechanisms of this inhibition remain to be fully established. Here, we report that the Us11 protein targetstripartite motifprotein 23 (TRIM23), which is a key regulator of autophagy-mediated antiviral defense mediated by TANK-binding kinase 1 (TBK1). In virus-infected cells, the Us11 protein drastically reduces the formation of autophagosomes mediated by TRIM23 or TBK1. This autophagy-inhibitory effect is attributable to the binding of the Us11 protein to the ARF domain in TRIM23. Furthermore, such interaction spatially excludes TBK1 from the TRIM23 complex that also contains heat shock protein 90 (Hsp90). When stably expressed alone in host cells, the Us11 protein recapitulates the observed phenotypes seen in cells infected with the US11-expressing or wild-type virus. Consistent with this, expression of the Us11 protein promotes HSV-1 growth, while expression of TRIM23 restricts HSV-1 replication in the absence of US11. Together, these results suggest that disruption of the TRIM23-TBK1 complex by the Us11 protein inhibits autophagy-mediated restriction of HSV-1 infection.IMPORTANCEAutophagy is an evolutionarily conserved process that restricts certain intracellular pathogens, including HSV-1. Although HSV-1 is well known to inhibit autophagy, little is known about the precise molecular mechanisms of autophagy inhibition. We demonstrate that the Us11 protein of HSV-1 spatially disrupts the TRIM23-TBK1 complex, which subsequently suppresses autophagy and autophagy-mediated virus restriction. Thus, expression of the Us11 protein facilitates HSV-1 replication. These data unveil new insight into viral escape from autophagy-mediated host restriction mechanisms.

scholarly journals Investigating the effect of Herpes Simplex Virus 1 Latency-Associated Non-Coding RNAs on the Human Neuronal Transcriptome

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Amy Jacobs ◽  
Ryan Mate ◽  
Martin Fritzsche ◽  
Peter O’Hare ◽  
Stacey Efstathiou
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Herpes Simplex Virus 1 ◽  
Significant Differential Expression ◽  
Human Neurons ◽  
Non Coding Rnas ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) is a prevalent neurotropic virus that persists for the host’s lifetime due to HSV-1 establishing latency in sensory neurons. During latency, the only abundantly transcribed HSV-1 gene is the latency-associated transcript (LAT), which is processed into the 1.5kb or 2.0kb major LAT intron and several microRNAs. These latency-associated non-coding RNAs (ncRNAs) have been reported to impact the establishment, maintenance and reactivation from latency. However, the molecular mechanisms of these ncRNAs are not fully characterised, especially in the context of human neurons. This study investigated how the latency-associated ncRNAs affect the human neuronal transcriptome. We developed an experimental system to deliver the latency-associated ncRNAs to human neurons, differentiated from SH-SY5Y neuroblastoma cells. The cells were infected with a replication-defective HSV-1 mutant, in1382, that establishes a quiescent infection in which LAT is strongly expressed. Alternatively, we utilised lentiviruses engineered to express the first 3.1kb of LAT, without or with mutations in splice sites that prevents splicing of the major LAT intron, or five HSV-1 microRNAs, shown to be abundant in latently infected human ganglia. Following RNA-Seq of uninfected versus infected or transduced SH-SY5Y cells, we identified 178 host genes that had significant differential expression in response to in1382 quiescent infection and lentivirus delivery of LAT or the latency-associated microRNAs. A subset of these were validated by PCR. This work provides insight into possible roles of the latency-associated ncRNAs in neuronal cell biology and latency that could aid future investigations examining how HSV-1 latency affects human neurons.

scholarly journals The Race between Host Antiviral Innate Immunity and the Immune Evasion Strategies of Herpes Simplex Virus 1

2020 ◽  
Vol 84 (4) ◽  
Author(s):  
Huifang Zhu ◽  
Chunfu Zheng
Keyword(s):  
Innate Immunity ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Stress Responses ◽  
Innate Immune Responses ◽  
Herpes Simplex Virus 1 ◽  
Cellular Survival ◽  
Simplex Virus ◽  
Antiviral Innate Immunity ◽  
Hsv 1

SUMMARY Herpes simplex virus 1 (HSV-1) is very successful in establishing acute and latent infections in humans by counteracting host antiviral innate immune responses. HSV-1 has evolved various strategies to evade host antiviral innate immunity and some cellular survival-associated pathways. Since there is still no vaccine available for HSV-1, a continuous update of information regarding the interaction between HSV-1 infection and the host antiviral innate immunity will provide novel insights to develop new therapeutic strategies for HSV-1 infection and its associated diseases. Here, we update recent studies about how HSV-1 evades the host antiviral innate immunity, specifically how HSV-1 proteins directly or indirectly target the adaptors in the antiviral innate immunity signaling pathways to downregulate the signal transduction. Additionally, some classical intracellular stress responses, which also play important roles in defense of viral invasion, will be discussed here. With a comprehensive review of evasion mechanisms of antiviral innate immunity by HSV-1, we will be able to develop potential new targets for therapies and a possible vaccine against HSV-1 infections.

scholarly journals Biogenesis of Extracellular Vesicles during Herpes Simplex Virus 1 Infection: Role of the CD63 Tetraspanin

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Christos Dogrammatzis ◽  
Thibaut Deschamps ◽  
Maria Kalamvoki
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Extracellular Vesicles ◽  
Host Factors ◽  
Herpes Simplex Virus 1 ◽  
Antiviral Responses ◽  
Infected Cells ◽  
Simplex Virus ◽  
In Cells ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) infections afflict more than 80% of the population worldwide. The virus primarily infects mucoepithelial cells and establishes latent reservoirs in neurons in sensory ganglia. Frequent reactivation has been linked to severe diseases, especially in immunocompromised individuals. Earlier, we reported that viral and host factors are packaged in extracellular vesicles (EVs) and delivered to uninfected cells, where they activate antiviral responses and restrict virus infection. Here, we interrogated the effect of HSV-1 infection on EV biogenesis. We found that HSV-1 infection causes a decrease in the amount of intracellular CD63 protein with a concomitant increase in extracellular CD63. This observation correlates with our previous finding that infected cells release more CD63-positive EVs than uninfected cells. The stimulation of CD63 exocytosis requires virus replication. CD63 is a member of the tetraspanin family of proteins that traffics between the plasma membrane and endosomal compartments and has a role in sorting cargo into the EVs. Previously, we reported that in cells depleted of CD63, HSV-1 virus yields increased, and here we provide data showing that in cells overexpressing CD63, HSV-1 virus yields decreased. Taken together, our data indicate that CD63 negatively impacts HSV-1 infection and that the CD63-positive EVs could control the dissemination of the virus in the host. Perhaps EV release by HSV-1-infected cells is a mechanism that controls virus dissemination.IMPORTANCEIntercellular communication, especially in neurons, largely relies on EVs, and modulation of EVs is known to impact physiological processes. Here, we present evidence that HSV-1 infection causes major alterations in the biogenesis of EVs, including an increase in their number and an increase in the CD63-positive population of EVs. These alterations result in an enrichment of the milieu of infection with EVs carrying signatures from infected cells. In addition to changes in the origin and type, EVs released by infected cells have differences in cargo, as they carry viral and host factors determined by the virus. The tetraspanin CD63 negatively impacts the infection, as demonstrated by CD63-knockdown and overexpression assays. A proposed mechanism involves the activation of antiviral responses in cells receiving CD63-positive EVs released by infected cells. Overall, HSV-1 causes major alterations in EVs that could contribute to HSV-1 persistence and pathogenesis.

scholarly journals Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Chenhe Su ◽  
Chunfu Zheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Signaling Pathway ◽  
Tegument Protein ◽  
Dna Sensing ◽  
Herpes Simplex Virus 1 ◽  
Antiviral Responses ◽  
Simplex Virus ◽  
First Time ◽  
Hsv 1

ABSTRACT Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway. Herpes simplex virus 1 (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. In the present study, we found that HSV-1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. Our results showed that wild-type (WT) HSV-1 infection could inhibit immunostimulatory DNA-induced activation of the IFN signaling pathway compared with the UL41-null mutant virus (R2621), and ectopic expression of UL41 decreased cGAS/STING-mediated IFN-β promoter activation and IFN-β production. Further study indicated that UL41 reduced the accumulation of cGAS to abrogate host recognition of viral DNA. In addition, stable knockdown of cGAS facilitated the replication of R2621 but not WT HSV-1. For the first time, HSV-1 UL41 was demonstrated to evade the cGAS/STING-mediated DNA-sensing pathway by degrading cGAS via its RNase activity. IMPORTANCE HSV-1 is well known for its ability to evade host antiviral responses and establish a lifelong latent infection while triggering reactivation and lytic infection under stress. Currently, whether HSV-1 evades the cytosolic DNA sensing and signaling is still poorly understood. In the present study, we found that tegument protein UL41 targeted the cGAS/STING-mediated cellular DNA-sensing pathway by selectively degrading cGAS mRNA. Knockdown of endogenous cGAS could facilitate the replication of R2621 but not WT HSV-1. Furthermore, UL41 was shown for the first time to act directly on cGAS. Findings in this study could provide new insights into the host-virus interaction and help develop new approaches against HSV-1.

scholarly journals Host and Viral Factors Involved in Nuclear Egress of Herpes Simplex Virus 1

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 754
Author(s):  
Jun Arii
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Nuclear Membrane ◽  
Molecular Mechanisms ◽  
Nucleocytoplasmic Transport ◽  
Herpes Simplex Virus 1 ◽  
Similar System ◽  
Nuclear Egress ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) replicates its genome and packages it into capsids within the nucleus. HSV-1 has evolved a complex mechanism of nuclear egress whereby nascent capsids bud on the inner nuclear membrane to form perinuclear virions that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytosol. The viral-encoded nuclear egress complex (NEC) plays a crucial role in this vesicle-mediated nucleocytoplasmic transport. Nevertheless, similar system mediates the movement of other cellular macromolecular complexes in normal cells. Therefore, HSV-1 may utilize viral proteins to hijack the cellular machinery in order to facilitate capsid transport. However, little is known about the molecular mechanisms underlying this phenomenon. This review summarizes our current understanding of the cellular and viral factors involved in the nuclear egress of HSV-1 capsids.

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