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Replication and Spread of Alphaherpesviruses

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 50910

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Prof. Dr. Stephen A. Rice

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Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA
Interests: Herpes simplex virus type-1 (HSV-1); viral gene expression; immediate-early proteins; post-transcriptional gene regulation; viral spread

Special Issue Information

Dear Colleagues,

Alphaherpesviruses comprise one of the three subfamilies of the Herpesviridae, a large group of nuclear-replicating, double-stranded DNA viruses that infect mammalian, avian, and reptilian species. This subfamily includes important human pathogens such as Herpes simplex virus types 1 and 2 and Varicella-zoster virus, as well as veterinary pathogens including Marek’s disease virus and Pseuodorabies virus. Similar to all other viruses, alphaherpesviruses must carry out the fundamental steps of the viral infectious cycle in order to replicate in their host cells. These steps include (but are not limited to) receptor-mediated cell entry, gene expression, genome replication, virion assembly, and particle egress. In addition, in order to propagate themselves in nature, progeny alphaherpesvirus particles must efficiently spread to new target cells in an infected host as well as to naive individuals in a host population. This Special Issue focuses on new and emerging findings relevant to the fundamental mechanisms that alphaherpesviruses use to replicate and spread in their host species. Such knowledge is important, not only to more fully understand these fascinating forms of life but also to develop novel strategies to prevent or limit the diseases that they cause.

Prof. Dr. Stephen A. Rice
Guest Editor

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Keywords

alphaherpesviruses
HSV-1
HSV-1
VZV
MDV
PRV
cell entry
viral gene expression
viral DNA replication
virion assembly
viral egress
viral spread
horizontal transmission

Published Papers (13 papers)

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Editorial

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3 pages, 166 KiB

Open AccessEditorial

Special Issue “Replication and Spread of Alphaherpesviruses”

by Stephen A. Rice

Viruses 2022, 14(8), 1652; https://0-doi-org.brum.beds.ac.uk/10.3390/v14081652 - 28 Jul 2022

Viewed by 1065

Abstract

Alphaherpesviruses, one of three sub-families of the Herpesviridae, are of keen interest to biomedical scientists for several reasons [...] Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

Research

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18 pages, 2079 KiB

Open AccessArticle

The In Vitro Replication, Spread, and Oncolytic Potential of Finnish Circulating Strains of Herpes Simplex Virus Type 1

by Kiira Kalke, Julius Orpana, Tuomas Lasanen, Olaya Esparta, Liisa M. Lund, Fanny Frejborg, Tytti Vuorinen, Henrik Paavilainen and Veijo Hukkanen

Viruses 2022, 14(6), 1290; https://0-doi-org.brum.beds.ac.uk/10.3390/v14061290 - 13 Jun 2022

Cited by 2 | Viewed by 2535

Abstract

Herpes simplex virus type 1 (HSV-1) is the only FDA- and EMA- approved oncolytic virus, and accordingly, many potential oncolytic HSVs (oHSV) are in clinical development. The utilized oHSV parental strains are, however, mostly based on laboratory reference strains, which may possess a compromised cytolytic capacity in contrast to circulating strains of HSV-1. Here, we assess the phenotype of thirty-six circulating HSV-1 strains from Finland to uncover their potential as oHSV backbones. First, we determined their capacity for cell-to-cell versus extracellular spread, to find strains with replication profiles favorable for each application. Second, to unfold the differences, we studied the genetic diversity of two relevant viral glycoproteins (gB/UL27, gI/US7). Third, we examined the oncolytic potential of the strains in cells representing glioma, lymphoma, and colorectal adenocarcinoma. Our results suggest that the phenotype of a circulating isolate, including the oncolytic potential, is highly related to the host cell type. Nevertheless, we identified isolates with increased oncolytic potential in comparison with the reference viruses across many or all of the studied cancer cell types. Our research emphasizes the need for careful selection of the backbone virus in early vector design, and it highlights the potential of clinical isolates as backbones in oHSV development. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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13 pages, 3565 KiB

Open AccessArticle

Plasma Membrane-Derived Liposomes Exhibit Robust Antiviral Activity against HSV-1

by Ilina Bhattacharya, Tejabhiram Yadavalli, David Wu and Deepak Shukla

Viruses 2022, 14(4), 799; https://0-doi-org.brum.beds.ac.uk/10.3390/v14040799 - 12 Apr 2022

Cited by 4 | Viewed by 1783

Abstract

Plasma membranes host a plethora of proteins and glycans on their outer surface that are exploited by viruses to enter the cells. In this study, we have utilized this property to limit a viral infection using plasma membrane-derived vesicles. We show that plasma membrane-derived liposomes are prophylactically and therapeutically competent at preventing herpes simplex virus type-1 (HSV-1) infection. Plasma membrane liposomes derived from human corneal epithelial (HCE) cells, which are natural targets of HSV-1 infection, as well as Vero and Chinese hamster ovary (CHO) cells were used in this study. Our study clearly demonstrates that HCE and Vero-derived cellular liposomes, which express the viral entry-specific cell surface protein receptors, exhibit robust antiviral activity especially when compared to CHO-derived liposomes, which lack the relevant HSV-1 entry receptors. Further experimentation of the plasma membrane-derived liposomes with HSV type-2 (HSV-2) and pseudorabies virus yielded similar results, indicating strong potential for the employment of these liposomes to study viral entry mechanisms in a cell free-environment. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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13 pages, 2378 KiB

Open AccessArticle

The Conserved Herpesviridae Protein Kinase (CHPK) of Gallid alphaherpesvirus 3 (GaHV3) Is Required for Horizontal Spread and Natural Infection in Chickens

by Andrea Krieter, Huai Xu, Haji Akbar, Taejoong Kim and Keith William Jarosinski

Viruses 2022, 14(3), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/v14030586 - 12 Mar 2022

Cited by 3 | Viewed by 2134

Abstract

We have formerly identified the conserved herpesvirus protein kinase (CHPK) as essential for horizontal transmission of Marek’s disease virus (MDV). Thus far, it has been confirmed that the mutation of the invariant lysine (K) of CHPKs abrogates kinase activity and that CHPK activity is required for MDV horizontal transmission. Since CHPK is conserved among all members of the Herpesviridae, we hypothesized that CHPK, and specifically its kinase activity, is important for the horizontal transmission of other herpesviruses. To test this hypothesis, we utilized our experimental and natural infection model in chickens with MD vaccine strain 301B/1 of Gallid alphaherpesvirus 3 (GaHV3). First, we mutated the invariant lysine (K) 157 of 301B/1 CHPK to alanine (A) and determined whether it was required for horizontal transmission. To confirm the requirement of 301B/1 CHPK activity for transmission, a rescued virus was generated in which the A157 was changed back to a K (A157K). Despite both the CHPK mutant (K157A) and rescuant (A157K) viruses having replication defects in vivo, only the CHPK mutant (K157A) was unable to spread to contact chickens, while both wild-type and rescuant (A157K) viruses transmitted efficiently, confirming the importance of CHPK activity for horizontal spread. The data confirm that CHPK is required for GaHV3 transmission and suggest that the requirement of avian CHPKs for natural infection is conserved. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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19 pages, 3412 KiB

Open AccessArticle

Stress Induced Transcription Factors Transactivate the Herpes Simplex Virus 1 Infected Cell Protein 27 (ICP27) Transcriptional Enhancer

by Jeffery B. Ostler and Clinton Jones

Viruses 2021, 13(11), 2296; https://0-doi-org.brum.beds.ac.uk/10.3390/v13112296 - 17 Nov 2021

Cited by 13 | Viewed by 2252

Abstract

Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons, including sensory neurons within trigeminal ganglia. During latency, lytic cycle viral gene expression is silenced. However, stressful stimuli can trigger reactivation from latency. The viral tegument protein, VP-16, transactivates all immediate early (IE) promoters during productive infection. Conversely, cellular factors are expected to trigger viral gene expression during early stages of reactivation from latency and in non-neuronal cells that do not support high levels of productive infection. The glucocorticoid receptor (GR), synthetic corticosteroid dexamethasone, and certain stress-induced transcription factors cooperatively transactivate infected cell protein 0 (ICP0) and ICP4 promoters. Since ICP27 protein expression is required for productive infection, we hypothesized that the ICP27 promoter is transactivated by stress-induced transcription factors. New studies have demonstrated that ICP27 enhancer sequences were transactivated by GR and Krüppel-like factor 15 (KLF15). Mutation of a consensus Sp1 binding site within ICP27 enhancer sequences impaired transactivation by GR and KLF15. Chromatin immunoprecipitation studies have demonstrated that GR and KLF15 occupy ICP27 promoter sequences during productive infection. Cells transfected with an ICP27 enhancer fragment revealed the GR and KLF15 occupancy of ICP27 enhancer sequences required the intact Sp1 binding site. Notably, GR and KLF15 form a feed-forward transcription loop in response to stress, suggesting these cellular factors promote viral replication following stressful stimuli. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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20 pages, 29087 KiB

Open AccessEditor’s ChoiceArticle

Herpes Simplex Virus 1 and 2 Infections during Differentiation of Human Cortical Neurons

by Petra Bergström, Edward Trybala, Charlotta E. Eriksson, Maria Johansson, Tugce Munise Satir, Sibylle Widéhn, Stefanie Fruhwürth, Wojciech Michno, Faisal Hayat Nazir, Jörg Hanrieder, Soren Riis Paludan, Lotta Agholme, Henrik Zetterberg and Tomas Bergström

Viruses 2021, 13(10), 2072; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102072 - 14 Oct 2021

Cited by 5 | Viewed by 2768

Abstract

Herpes simplex virus 1 (HSV-1) and 2 (HSV-2) can infect the central nervous system (CNS) with dire consequences; in children and adults, HSV-1 may cause focal encephalitis, while HSV-2 causes meningitis. In neonates, both viruses can cause severe, disseminated CNS infections with high mortality rates. Here, we differentiated human induced pluripotent stem cells (iPSCs) towards cortical neurons for infection with clinical CNS strains of HSV-1 or HSV-2. Progenies from both viruses were produced at equal quantities in iPSCs, neuroprogenitors and cortical neurons. HSV-1 and HSV-2 decreased viability of neuroprogenitors by 36.0% and 57.6% (p < 0.0001), respectively, 48 h post-infection, while cortical neurons were resilient to infection by both viruses. However, in these functional neurons, both HSV-1 and HSV-2 decreased gene expression of two markers of synaptic activity, CAMK2B and ARC, and affected synaptic activity negatively in multielectrode array experiments. However, unaltered secretion levels of the neurodegeneration markers tau and NfL suggested intact axonal integrity. Viral replication of both viruses was found after six days, coinciding with 6-fold and 22-fold increase in gene expression of cellular RNA polymerase II by HSV-1 and HSV-2, respectively. Our results suggest a resilience of human cortical neurons relative to the replication of HSV-1 and HSV-2. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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14 pages, 2846 KiB

Open AccessArticle

The Requirement of Glycoprotein C for Interindividual Spread Is Functionally Conserved within the Alphaherpesvirus Genus (Mardivirus), but Not the Host (Gallid)

by Widaliz Vega-Rodriguez, Nagendraprabhu Ponnuraj, Maricarmen Garcia and Keith W. Jarosinski

Viruses 2021, 13(8), 1419; https://doi.org/10.3390/v13081419 - 21 Jul 2021

Cited by 4 | Viewed by 1786

Abstract

Marek’s disease (MD) in chickens is caused by Gallid alphaherpesvirus 2, better known as MD herpesvirus (MDV). Current vaccines do not block interindividual spread from chicken-to-chicken, therefore, understanding MDV interindividual spread provides important information for the development of potential therapies to protect against MD, while also providing a natural host to study herpesvirus dissemination. It has long been thought that glycoprotein C (gC) of alphaherpesviruses evolved with their host based on their ability to bind and inhibit complement in a species-selective manner. Here, we tested the functional importance of gC during interindividual spread and host specificity using the natural model system of MDV in chickens through classical compensation experiments. By exchanging MDV gC with another chicken alphaherpesvirus (Gallid alphaherpesvirus 1 or infectious laryngotracheitis virus; ILTV) gC, we determined that ILTV gC could not compensate for MDV gC during interindividual spread. In contrast, exchanging turkey herpesvirus (Meleagrid alphaherpesvirus 1 or HVT) gC could compensate for chicken MDV gC. Both ILTV and MDV are Gallid alphaherpesviruses; however, ILTV is a member of the Iltovirus genus, while MDV is classified as a Mardivirus along with HVT. These results suggest that gC is functionally conserved based on the virus genera (Mardivirus vs. Iltovirus) and not the host (Gallid vs. Meleagrid). Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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10 pages, 2503 KiB

Open AccessArticle

Histopathological Analysis of Adrenal Glands after Simian Varicella Virus Infection

by Christy S. Niemeyer, Teresa Mescher, Rocio Griggs, David J. Orlicky, Gregory K. Wilkerson, Andrew N. Bubak, James E. Hassell, Jr., Brittany Feia, Ravi Mahalingam, Vicki Traina-Dorge and Maria A. Nagel

Viruses 2021, 13(7), 1245; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071245 - 26 Jun 2021

Cited by 4 | Viewed by 9206

Abstract

Latent varicella zoster virus (VZV) has been detected in human adrenal glands, raising the possibility of virus-induced adrenal damage and dysfunction during primary infection or reactivation. Rare cases of bilateral adrenal hemorrhage and insufficiency associated with VZV reactivation have been reported. Since there is no animal model for VZV infection of adrenal glands, we obtained adrenal glands from two non-human primates (NHPs) that spontaneously developed varicella from primary simian varicella virus (SVV) infection, the NHP VZV homolog. Histological and immunohistochemical analysis revealed SVV antigen and DNA in the adrenal medulla and cortex of both animals. Adrenal glands were observed to have Cowdry A inclusion bodies, cellular necrosis, multiple areas of hemorrhage, and varying amounts of polymorphonuclear cells. No specific association of SVV antigen with βIII-tubulin-positive nerve fibers was found. Overall, we found that SVV can productively infect NHP adrenal glands, and is associated with inflammation, hemorrhage, and cell death. These findings suggest that further studies are warranted to examine the contribution of VZV infection to human adrenal disease. This study also suggests that VZV infection may present itself as acute adrenal dysfunction with “long-hauler” symptoms of fatigue, weakness, myalgias/arthralgias, and hypotension. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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Review

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17 pages, 3082 KiB

Open AccessReview

Well Put Together—A Guide to Accessorizing with the Herpesvirus gH/gL Complexes

by Gonzalo L. Gonzalez-Del Pino and Ekaterina E. Heldwein

Viruses 2022, 14(2), 296; https://0-doi-org.brum.beds.ac.uk/10.3390/v14020296 - 30 Jan 2022

Cited by 6 | Viewed by 3435

Abstract

Herpesviruses are enveloped, double-stranded DNA viruses that infect a variety of hosts across the animal kingdom. Nine of these establish lifelong infections in humans, for which there are no cures and few vaccine or treatment options. Like all enveloped viruses, herpesviruses enter cells by fusing their lipid envelopes with a host cell membrane. Uniquely, herpesviruses distribute the functions of receptor engagement and membrane fusion across a diverse cast of glycoproteins. Two glycoprotein complexes are conserved throughout the three herpesvirus subfamilies: the trimeric gB that functions as a membrane fusogen and the heterodimeric gH/gL, the role of which is less clearly defined. Here, we highlight the conserved and divergent functions of gH/gL across the three subfamilies of human herpesviruses by comparing its interactions with a broad range of accessory viral proteins, host cell receptors, and neutralizing or inhibitory antibodies. We propose that the intrinsic structural plasticity of gH/gL enables it to function as a signal integration machine that can accept diverse regulatory inputs and convert them into a “trigger” signal that activates the fusogenic ability of gB. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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19 pages, 2190 KiB

Open AccessReview

Replication and Spread of Oncolytic Herpes Simplex Virus in Solid Tumors

by Bangxing Hong, Upasana Sahu, Matthew P. Mullarkey and Balveen Kaur

Viruses 2022, 14(1), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/v14010118 - 10 Jan 2022

Cited by 13 | Viewed by 4631

Abstract

Oncolytic herpes simplex virus (oHSV) is a highly promising treatment for solid tumors. Intense research and development efforts have led to first-in-class approval for an oHSV for melanoma, but barriers to this promising therapy still exist that limit efficacy. The process of infection, replication and transmission of oHSV in solid tumors is key to obtaining a good lytic destruction of infected cancer cells to kill tumor cells and release tumor antigens that can prime anti-tumor efficacy. Intracellular tumor cell signaling and tumor stromal cells present multiple barriers that resist oHSV activity. Here, we provide a review focused on oncolytic HSV and the essential viral genes that allow for virus replication and spread in order to gain insight into how manipulation of these pathways can be exploited to potentiate oHSV infection and replication among tumor cells. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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15 pages, 1461 KiB

Open AccessReview

Release of HSV-1 Cell-Free Virions: Mechanisms, Regulation, and Likely Role in Human-Human Transmission

by Stephen A. Rice

Viruses 2021, 13(12), 2395; https://0-doi-org.brum.beds.ac.uk/10.3390/v13122395 - 30 Nov 2021

Cited by 10 | Viewed by 5636

Abstract

Herpes simplex virus type 1, or HSV-1, is a widespread human pathogen that replicates in epithelial cells of the body surface and then establishes latent infection in peripheral neurons. When HSV-1 replicates, viral progeny must be efficiently released to spread infection to new target cells. Viral spread occurs via two major routes. In cell-cell spread, progeny virions are delivered directly to cellular junctions, where they infect adjacent cells. In cell-free release, progeny virions are released into the extracellular milieu, potentially allowing the infection of distant cells. Cell-cell spread of HSV-1 has been well studied and is known to be important for in vivo infection and pathogenesis. In contrast, HSV-1 cell-free release has received less attention, and its significance to viral biology is unclear. Here, I review the mechanisms and regulation of HSV-1 cell-free virion release. Based on knowledge accrued in other herpesviral systems, I argue that HSV-1 cell-free release is likely to be tightly regulated in vivo. Specifically, I hypothesize that this process is generally suppressed as the virus replicates within the body, but activated to high levels at sites of viral reactivation, such as the oral mucosa and skin, in order to promote efficient transmission of HSV-1 to new human hosts. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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15 pages, 2062 KiB

Open AccessReview

HSV-1 DNA Replication—Coordinated Regulation by Viral and Cellular Factors

by Jessica E. Packard and Jill A. Dembowski

Viruses 2021, 13(10), 2015; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102015 - 07 Oct 2021

Cited by 27 | Viewed by 8402

Abstract

DNA replication is an integral step in the herpes simplex virus type 1 (HSV-1) life cycle that is coordinated with the cellular DNA damage response, repair and recombination of the viral genome, and viral gene transcription. HSV-1 encodes its own DNA replication machinery, including an origin binding protein (UL9), single-stranded DNA binding protein (ICP8), DNA polymerase (UL30), processivity factor (UL42), and a helicase/primase complex (UL5/UL8/UL52). In addition, HSV-1 utilizes a combination of accessory viral and cellular factors to coordinate viral DNA replication with other viral and cellular processes. The purpose of this review is to outline the roles of viral and cellular proteins in HSV-1 DNA replication and replication-coupled processes, and to highlight how HSV-1 may modify and adapt cellular proteins to facilitate productive infection. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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17 pages, 652 KiB

Open AccessReview

A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery

by Thomas Hennig, Lara Djakovic, Lars Dölken and Adam W. Whisnant

Viruses 2021, 13(9), 1836; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091836 - 14 Sep 2021

Cited by 10 | Viewed by 3425

Abstract

During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional control. This review summarizes the array of impacts that HSV has on RNA Polymerase (Pol) II, which transcribes all mRNA in infected cells. We discuss alterations in Pol II holoenzymes, post-translational modifications, and how viral proteins regulate specific activities such as promoter-proximal pausing, splicing, histone repositioning, and termination with respect to host genes. Recent technological innovations that have reshaped our understanding of previous observations are summarized in detail, along with specific research directions and technical considerations for future studies. Full article

(This article belongs to the Special Issue Replication and Spread of Alphaherpesviruses)

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