Herpes Simplex Virus: A Versatile Tool for Insights Into Evolution, Gene Delivery, and Tumor Immunotherapy

Herpesviruses are prevalent throughout the animal kingdom, and they have coexisted and coevolved along with their host species for millions of years. Herpesviruses carry a large (120-230 kb) double-stranded DNA genome surrounded by a protein capsid, a tegument layer consisting of viral and host proteins, and a lipid bilayer envelope with surface glycoproteins. A key characteristic of these viruses is their ability to enter a latent state following primary infection, allowing them to evade the host’s immune system and persist permanently. Herpesviruses can reactivate from their dormant state, usually during times of stress or when the host’s immune responses are impaired. While herpesviruses can cause complications with severe disease in immune-compromised people, most of the population experiences few ill effects from herpesvirus infections. Indeed, herpes simplex virus 1 (HSV-1) in particular has several features that make it an attractive tool for therapeutic gene delivery. Herpes simplex virus 1 targets and infects specific cell types, such as epithelial cells and neurons. The HSV-1 genome can also accommodate large insertions of up to 14 kb. The HSV-1-based vectors have already achieved success for the oncolytic treatment of melanoma. In addition to serving as a vehicle for therapeutic gene delivery and targeted cell lysis, comparative genomics of herpesviruses HSV-1 and 2 has revealed valuable information about the evolutionary history of both viruses and their hosts. This review focuses on the adaptability of HSV-1 as an instrument for gene delivery and an evolutionary marker. Overall, HSV-1 shows great promise as a tool for treating human disease and studying human migration patterns, disease outbreaks, and evolution.

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

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140579 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-020-77725-4 ◽

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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Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

Viruses ◽

10.3390/v13020196 ◽

2021 ◽

Vol 13 (2) ◽

pp. 196

Author(s):

Sara Artusi ◽

Emanuela Ruggiero ◽

Matteo Nadai ◽

Beatrice Tosoni ◽

Rosalba Perrone ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Dna Replication ◽

Herpes Simplex ◽

Antiviral Activity ◽

Herpes Simplex Virus 1 ◽

Tem Analysis ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

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Herpes Simplex Virus 1 UL34 Protein Regulates the Global Architecture of the Endoplasmic Reticulum in Infected Cells

Journal of Virology ◽

10.1128/jvi.00271-17 ◽

2017 ◽

Vol 91 (12) ◽

Cited By ~ 10

Author(s):

Fumio Maeda ◽

Jun Arii ◽

Yoshitaka Hirohata ◽

Yuhei Maruzuru ◽

Naoto Koyanagi ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Null Mutation ◽

Wild Type ◽

Herpes Simplex Virus 1 ◽

Nuclear Egress ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Upon herpes simplex virus 1 (HSV-1) infection, the CD98 heavy chain (CD98hc) is redistributed around the nuclear membrane (NM), where it promotes viral de-envelopment during the nuclear egress of nucleocapsids. In this study, we attempted to identify the factor(s) involved in CD98hc accumulation and demonstrated the following: (i) the null mutation of HSV-1 UL34 caused specific dispersion throughout the cytoplasm of CD98hc and the HSV-1 de-envelopment regulators, glycoproteins B and H (gB and gH); (ii) as observed with CD98hc, gB, and gH, wild-type HSV-1 infection caused redistribution of the endoplasmic reticulum (ER) markers calnexin and ERp57 around the NM, whereas the UL34-null mutation caused cytoplasmic dispersion of these markers; (iii) the ER markers colocalized efficiently with CD98hc, gB, and gH in the presence and absence of UL34 in HSV-1-infected cells; (iv) at the ultrastructural level, wild-type HSV-1 infection caused ER compression around the NM, whereas the UL34-null mutation caused cytoplasmic dispersion of the ER; and (v) the UL34-null mutation significantly decreased the colocalization efficiency of lamin protein markers of the NM with CD98hc and gB. Collectively, these results indicate that HSV-1 infection causes redistribution of the ER around the NM, with resulting accumulation of ER-associated CD98hc, gB, and gH around the NM and that UL34 is required for ER redistribution, as well as for efficient recruitment to the NM of the ER-associated de-envelopment factors. Our study suggests that HSV-1 induces remodeling of the global ER architecture for recruitment of regulators mediating viral nuclear egress to the NM. IMPORTANCE The ER is an important cellular organelle that exists as a complex network extending throughout the cytoplasm. Although viruses often remodel the ER to facilitate viral replication, information on the effects of herpesvirus infections on ER morphological integrity is limited. Here, we showed that HSV-1 infection led to compression of the global ER architecture around the NM, resulting in accumulation of ER-associated regulators associated with nuclear egress of HSV-1 nucleocapsids. We also identified HSV-1 UL34 as a viral factor that mediated ER remodeling. Furthermore, we demonstrated that UL34 was required for efficient targeting of these regulators to the NM. To our knowledge, this is the first report showing that a herpesvirus remodels ER global architecture. Our study also provides insight into the mechanism by which the regulators for HSV-1 nuclear egress are recruited to the NM, where this viral event occurs.

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Structural Variability of the Herpes Simplex Virus 1 GenomeIn VitroandIn Vivo

Journal of Virology ◽

10.1128/jvi.00223-12 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8592-8601 ◽

Cited By ~ 9

Author(s):

Charlotte Mahiet ◽

Ayla Ergani ◽

Nicolas Huot ◽

Nicolas Alende ◽

Ahmed Azough ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Considerable Proportion ◽

Inverted Repeats ◽

Herpes Simplex Virus 1 ◽

Cell Extracts ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus 1 (HSV-1) is a human pathogen that leads to recurrent facial-oral lesions. Its 152-kb genome is organized in two covalently linked segments, each composed of a unique sequence flanked by inverted repeats. Replication of the HSV-1 genome produces concatemeric molecules in which homologous recombination events occur between the inverted repeats. This mechanism leads to four genome isomers (termed P, IS, IL, and ILS) that differ in the relative orientations of their unique fragments. Molecular combing analysis was performed on DNA extracted from viral particles and BSR, Vero, COS-7, and Neuro-2a cells infected with either strain SC16 or KOS of HSV-1, as well as from tissues of experimentally infected mice. Using fluorescence hybridization, isomers were repeatedly detected and distinguished and were accompanied by a large proportion of noncanonical forms (40%). In both cell and viral-particle extracts, the distributions of the four isomers were statistically equivalent, except for strain KOS grown in Vero and Neuro-2a cells, in which P and IS isomers were significantly overrepresented. In infected cell extracts, concatemeric molecules as long as 10 genome equivalents were detected, among which, strikingly, the isomer distributions were equivalent, suggesting that any such imbalance may occur during encapsidation.In vivo, for strain KOS-infected trigeminal ganglia, an unbalanced distribution distinct from the onein vitrowas observed, along with a considerable proportion of noncanonical assortment.

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A Functional Interaction between Herpes Simplex Virus 1 Glycoprotein gH/gL Domains I and II and gD Is Defined by Using Alphaherpesvirus gH and gL Chimeras

Journal of Virology ◽

10.1128/jvi.00740-15 ◽

2015 ◽

Vol 89 (14) ◽

pp. 7159-7169 ◽

Cited By ~ 15

Author(s):

Qing Fan ◽

Richard Longnecker ◽

Sarah A. Connolly

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Host Cell ◽

Current Model ◽

Viral Envelope ◽

Functional Interaction ◽

Herpes Simplex Virus 1 ◽

Homotypic Interaction ◽

Simplex Virus ◽

Hsv 1

ABSTRACTWhereas most viruses require only a single protein to bind to and fuse with cells, herpesviruses use multiple glycoproteins to mediate virus entry, and thus communication among these proteins is required. For most alphaherpesviruses, the minimal set of viral proteins required for fusion with the host cell includes glycoproteins gD, gB, and a gH/gL heterodimer. In the current model of entry, gD binds to a cellular receptor and transmits a signal to gH/gL. This signal then triggers gB, the conserved fusion protein, to insert into the target membrane and refold to merge the viral and cellular membranes. We previously demonstrated that gB homologs from two alphaherpesviruses, herpes simplex virus 1 (HSV-1) and saimiriine herpesvirus 1 (SaHV-1), were interchangeable. In contrast, neither gD nor gH/gL functioned with heterotypic entry glycoproteins, indicating that gD and gH/gL exhibit an essential type-specific functional interaction. To map this homotypic interaction site on gH/gL, we generated HSV-1/SaHV-1 gH and gL chimeras. The functional interaction with HSV-1 gD mapped to the N-terminal domains I and II of the HSV-1 gH ectodomain. The core of HSV-1 gL that interacts with gH also was required for functional homotypic interaction. The N-terminal gH/gL domains I and II are the least conserved and may have evolved to support species-specific glycoprotein interactions.IMPORTANCEThe first step of the herpesvirus life cycle is entry into a host cell. A coordinated interaction among multiple viral glycoproteins is required to mediate fusion of the viral envelope with the cell membrane. The details of how these glycoproteins interact to trigger fusion are unclear. By swapping the entry glycoproteins of two alphaherpesviruses (HSV-1 and SaHV-1), we previously demonstrated a functional homotypic interaction between gD and gH/gL. To define the gH and gL requirements for homotypic interaction, we evaluated the function of a panel of HSV-1/SaHV-1 gH and gL chimeras. We demonstrate that domains I and II of HSV-1 gH are sufficient to promote a functional, albeit reduced, interaction with HSV-1 gD. These findings contribute to our model of how the entry glycoproteins cooperate to mediate herpesvirus entry into the cell.

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Simultaneous Tracking of Capsid, Tegument, and Envelope Protein Localization in Living Cells Infected with Triply Fluorescent Herpes Simplex Virus 1

Journal of Virology ◽

10.1128/jvi.02681-07 ◽

2008 ◽

Vol 82 (11) ◽

pp. 5198-5211 ◽

Cited By ~ 98

Author(s):

Ken Sugimoto ◽

Masashi Uema ◽

Hiroshi Sagara ◽

Michiko Tanaka ◽

Tetsutaro Sata ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Envelope Protein ◽

Fluorescent Proteins ◽

Protein Localization ◽

Envelope Proteins ◽

Herpes Simplex Virus 1 ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

ABSTRACT We report here the construction of a triply fluorescent-tagged herpes simplex virus 1 (HSV-1) expressing capsid protein VP26, tegument protein VP22, and envelope protein gB as fusion proteins with monomeric yellow, red, and cyan fluorescent proteins, respectively. The recombinant virus enabled us to monitor the dynamics of these capsid, tegument, and envelope proteins simultaneously in the same live HSV-1-infected cells and to visualize single extracellular virions with three different fluorescent emissions. In Vero cells infected by the triply fluorescent virus, multiple cytoplasmic compartments were found to be induced close to the basal surfaces of the infected cells (the adhesion surfaces of the infected cells on the solid growth substrate). Major capsid, tegument, and envelope proteins accumulated and colocalized in the compartments, as did marker proteins for the trans-Golgi network (TGN) which has been implicated to be the site of HSV-1 secondary envelopment. Moreover, formation of the compartments was correlated with the dynamic redistribution of the TGN proteins induced by HSV-1 infection. These results suggest that HSV-1 infection causes redistribution of TGN membranes to form multiple cytoplasmic compartments, possibly for optimal secondary envelopment. This is the first real evidence for the assembly of all three types of herpesvirus proteins—capsid, tegument, and envelope membrane proteins—in TGN.

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