New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research

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

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 31178

Special Issue Editor

Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB‎, Canada
Interests: Kaposi’s sarcoma-associated herpesvirus (KSHV); virus-host interactions; processing bodies; mRNA decay; autophagy; antiviral responses; endothelial cells

Special Issue Information

Dear Colleagues,

Discovered in 1994, Kaposi’s sarcoma-associated herpesvirus (KSHV) is one of seven oncogenic viruses and one of two herpesviruses associated with human cancer. Unlike small DNA tumour viruses, KSHV is not constrained by genetic economy. With over 85 protein-coding regions (that we know of), this herpesvirus is a master manipulator.  KSHV deregulates antiviral responses, hijacks stress signaling and metabolic pathways, elicits aberrant cell proliferation and induces angiogenesis while reprogramming immune responses so that the virus can persist in a chronic latent state. Such complex virus-host interplay must be understood in molecular detail if we seek to intervene and treat these chronic infections without causing harm. In addition, as has so often been the case in the past, understanding how viruses manipulate and subvert our host defenses provides a window into the complexities of immune system regulation.

With this Special Issue of Viruses, we highlight recent developments in KSHV biology, including but not limited to mechanisms of virus-host interaction, viral immune evasion, viral tumorigenesis, latent versus lytic life cycle regulation, KSHV animal models, and new tools or methodologies for KSHV research. 

Dr. Jennifer Corcoran
Guest Editor

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Keywords

  • Kaposi’s sarcoma-associated herpesvirus
  • virus-host interactions
  • viral immune evasion
  • viral tumorigenesis
  • KSHV animal models
  • latent-lytic switch
  • KSHV tool development
  • methods for KSHV research

Published Papers (8 papers)

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Research

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14 pages, 9308 KiB  
Article
CRISPR Interference Efficiently Silences Latent and Lytic Viral Genes in Kaposi’s Sarcoma-Associated Herpesvirus-Infected Cells
by Kevin Brackett, Ameera Mungale, Mary Lopez-Isidro, Duncan A. Proctor, Guillermo Najarro and Carolina Arias
Viruses 2021, 13(5), 783; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050783 - 28 Apr 2021
Cited by 3 | Viewed by 2499
Abstract
Uncovering viral gene functions requires the modulation of gene expression through overexpression or loss-of-function. CRISPR interference (CRISPRi), a modification of the CRISPR-Cas9 gene editing technology, allows specific and efficient transcriptional silencing without genetic ablation. CRISPRi has been used to silence eukaryotic and prokaryotic [...] Read more.
Uncovering viral gene functions requires the modulation of gene expression through overexpression or loss-of-function. CRISPR interference (CRISPRi), a modification of the CRISPR-Cas9 gene editing technology, allows specific and efficient transcriptional silencing without genetic ablation. CRISPRi has been used to silence eukaryotic and prokaryotic genes at the single-gene and genome-wide levels. Here, we report the use of CRISPRi to silence latent and lytic viral genes, with an efficiency of ~80–90%, in epithelial and B-cells carrying multiple copies of the Kaposi’s sarcoma-associated herpesvirus (KSHV) genome. Our results validate CRISPRi for the analysis of KSHV viral elements, providing a functional genomics tool for studying virus–host interactions. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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15 pages, 4131 KiB  
Article
The Portal Vertex of KSHV Promotes Docking of Capsids at the Nuclear Pores
by Daniela Dünn-Kittenplon, Asaf Ashkenazy-Titelman, Inna Kalt, Jean-Paul Lellouche, Yaron Shav-Tal and Ronit Sarid
Viruses 2021, 13(4), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040597 - 31 Mar 2021
Cited by 7 | Viewed by 2216
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related herpesvirus. Like other herpesviruses, the KSHV icosahedral capsid includes a portal vertex, composed of 12 protein subunits encoded by open reading frame (ORF) 43, which enables packaging and release of the viral genome into the nucleus [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related herpesvirus. Like other herpesviruses, the KSHV icosahedral capsid includes a portal vertex, composed of 12 protein subunits encoded by open reading frame (ORF) 43, which enables packaging and release of the viral genome into the nucleus through the nuclear pore complex (NPC). Capsid vertex-specific component (CVSC) tegument proteins, which directly mediate docking at the NPCs, are organized on the capsid vertices and are enriched on the portal vertex. Whether and how the portal vertex is selected for docking at the NPC is unknown. Here, we investigated the docking of incoming ORF43-null KSHV capsids at the NPCs, and describe a significantly lower fraction of capsids attached to the nuclear envelope compared to wild-type (WT) capsids. Like WT capsids, nuclear envelope-associated ORF43-null capsids co-localized with different nucleoporins (Nups) and did not detach upon salt treatment. Inhibition of nuclear export did not alter WT capsid docking. As ORF43-null capsids exhibit lower extent of association with the NPCs, we conclude that although not essential, the portal has a role in mediating the interaction of the CVSC proteins with Nups, and suggest a model whereby WT capsids can dock at the nuclear envelope through a non-portal penton vertex, resulting in an infection ‘dead end’. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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16 pages, 1507 KiB  
Article
An Update of the Virion Proteome of Kaposi Sarcoma-Associated Herpesvirus
by Ramina Nabiee, Basir Syed, Jesus Ramirez Castano, Rukhsana Lalani and Jennifer E. Totonchy
Viruses 2020, 12(12), 1382; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121382 - 02 Dec 2020
Cited by 9 | Viewed by 3677
Abstract
The virion proteins of Kaposi sarcoma-associated herpesvirus (KSHV) were initially characterized in 2005 in two separate studies that combined the detection of 24 viral proteins and a few cellular components via LC-MS/MS or MALDI-TOF. Despite considerable advances in the sensitivity and specificity of [...] Read more.
The virion proteins of Kaposi sarcoma-associated herpesvirus (KSHV) were initially characterized in 2005 in two separate studies that combined the detection of 24 viral proteins and a few cellular components via LC-MS/MS or MALDI-TOF. Despite considerable advances in the sensitivity and specificity of mass spectrometry instrumentation in recent years, leading to significantly higher yields in detections, the KSHV virion proteome has not been revisited. In this study, we have re-examined the protein composition of purified KSHV virions via ultra-high resolution Qq time-of-flight mass spectrometry (UHR-QqTOF). Our results confirm the detection of all previously reported virion proteins, in addition to 17 other viral proteins, some of which have been characterized as virion-associated using other methods, and 10 novel proteins identified as virion-associated for the first time in this study. These results add KSHV ORF9, ORF23, ORF35, ORF48, ORF58, ORF72/vCyclin, K3, K9/vIRF1, K10/vIRF4, and K10.5/vIRF3 to the list of KSHV proteins that can be incorporated into virions. The addition of these proteins to the KSHV virion proteome provides novel and important insight into early events in KSHV infection mediated by virion-associated proteins. Data are available via ProteomeXchange with identifier PXD022626. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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14 pages, 5494 KiB  
Article
Kaposi’s Sarcoma-Associated Herpesvirus Reactivation by Targeting of a dCas9-Based Transcription Activator to the ORF50 Promoter
by Endrit Elbasani, Francesca Falasco, Silvia Gramolelli, Veijo Nurminen, Thomas Günther, Jere Weltner, Diego Balboa, Adam Grundhoff, Timo Otonkoski and Päivi M. Ojala
Viruses 2020, 12(9), 952; https://0-doi-org.brum.beds.ac.uk/10.3390/v12090952 - 27 Aug 2020
Cited by 3 | Viewed by 2865
Abstract
CRISPR activation (CRISPRa) has revealed great potential as a tool to modulate the expression of targeted cellular genes. Here, we successfully applied the CRISPRa system to trigger the Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation in latently infected cells by selectively activating ORF50 gene directly [...] Read more.
CRISPR activation (CRISPRa) has revealed great potential as a tool to modulate the expression of targeted cellular genes. Here, we successfully applied the CRISPRa system to trigger the Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation in latently infected cells by selectively activating ORF50 gene directly from the virus genome. We found that a nuclease-deficient Cas9 (dCas9) fused to a destabilization domain (DD) and 12 copies of the VP16 activation domain (VP192) triggered a more efficient KSHV lytic cycle and virus production when guided to two different sites on the ORF50 promoter, instead of only a single site. To our surprise, the virus reactivation induced by binding of the stable DD-dCas9-VP192 on the ORF50 promoter was even more efficient than reactivation induced by ectopic expression of ORF50. This suggests that recruitment of additional transcriptional activators to the ORF50 promoter, in addition to ORF50 itself, are needed for the efficient virus production. Further, we show that CRISPRa can be applied to selectively express the early lytic gene, ORF57, without disturbing the viral latency. Therefore, CRISPRa-based systems can be utilized to facilitate virus–host interaction studies by controlling the expression of not only cellular but also of specific KSHV genes. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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Review

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18 pages, 1148 KiB  
Review
Cytokine-Targeted Therapeutics for KSHV-Associated Disease
by Nedaa Alomari and Jennifer Totonchy
Viruses 2020, 12(10), 1097; https://0-doi-org.brum.beds.ac.uk/10.3390/v12101097 - 28 Sep 2020
Cited by 21 | Viewed by 3217
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a significant inflammatory component, current therapy for KSHV-associated disease is associated with significant off-target effects. However, recent advances in our understanding of the pathogenesis of KSHV have produced new insight into the use of cytokines as potential therapeutic targets. Better understanding of the role of cytokines during KSHV infection and tumorigenesis may lead to new preventive or therapeutic strategies to limit KSHV spread and improve clinical outcomes. The cytokines that appear to be promising candidates as KSHV antiviral therapies include interleukins 6, 10, and 12 as well as interferons and tumor necrosis factor-family cytokines. This review explores our current understanding of the roles that cytokines play in promoting KSHV infection and tumorigenesis, and summarizes the current use of cytokines as therapeutic targets in KSHV-associated diseases. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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20 pages, 3415 KiB  
Review
Regulation of KSHV Latency and Lytic Reactivation
by Grant Broussard and Blossom Damania
Viruses 2020, 12(9), 1034; https://doi.org/10.3390/v12091034 - 17 Sep 2020
Cited by 53 | Viewed by 6465
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three malignancies— Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three malignancies— Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and a replicative lytic phase. While the establishment of latency enables persistent KSHV infection and evasion of the host immune system, lytic replication is essential for the dissemination of the virus between hosts and within the host itself. The transition between these phases, known as lytic reactivation, is controlled by a complex set of environmental, host, and viral factors. The effects of these various factors converge on the regulation of two KSHV proteins whose functions facilitate each phase of the viral life cycle—latency-associated nuclear antigen (LANA) and the master switch of KSHV reactivation, replication and transcription activator (RTA). This review presents the current understanding of how the transition between the phases of the KSHV life cycle is regulated, how the various phases contribute to KSHV pathogenesis, and how the viral life cycle can be exploited as a therapeutic target. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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20 pages, 1262 KiB  
Review
Stealing the Show: KSHV Hijacks Host RNA Regulatory Pathways to Promote Infection
by Daniel Macveigh-Fierro, William Rodriguez, Jacob Miles and Mandy Muller
Viruses 2020, 12(9), 1024; https://0-doi-org.brum.beds.ac.uk/10.3390/v12091024 - 14 Sep 2020
Cited by 5 | Viewed by 3677
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) induces life-long infections and has evolved many ways to exert extensive control over its host’s transcriptional and post-transcriptional machinery to gain better access to resources and dampened immune sensing. The hallmark of this takeover is how KSHV reshapes RNA [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) induces life-long infections and has evolved many ways to exert extensive control over its host’s transcriptional and post-transcriptional machinery to gain better access to resources and dampened immune sensing. The hallmark of this takeover is how KSHV reshapes RNA fate both to control expression of its own gene but also that of its host. From the nucleus to the cytoplasm, control of RNA expression, localization, and decay is a process that is carefully tuned by a multitude of factors and that can adapt or react to rapid changes in the environment. Intriguingly, it appears that KSHV has found ways to co-opt each of these pathways for its own benefit. Here we provide a comprehensive review of recent work in this area and in particular recent advances on the post-transcriptional modifications front. Overall, this review highlights the myriad of ways KSHV uses to control RNA fate and gathers novel insights gained from the past decade of research at the interface of RNA biology and the field of KSHV research. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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33 pages, 3006 KiB  
Review
The bZIP Proteins of Oncogenic Viruses
by Madeleine L. Stolz and Craig McCormick
Viruses 2020, 12(7), 757; https://0-doi-org.brum.beds.ac.uk/10.3390/v12070757 - 14 Jul 2020
Cited by 9 | Viewed by 5631
Abstract
Basic leucine zipper (bZIP) transcription factors (TFs) govern diverse cellular processes and cell fate decisions. The hallmark of the leucine zipper domain is the heptad repeat, with leucine residues at every seventh position in the domain. These leucine residues enable homo- and heterodimerization [...] Read more.
Basic leucine zipper (bZIP) transcription factors (TFs) govern diverse cellular processes and cell fate decisions. The hallmark of the leucine zipper domain is the heptad repeat, with leucine residues at every seventh position in the domain. These leucine residues enable homo- and heterodimerization between ZIP domain α-helices, generating coiled-coil structures that stabilize interactions between adjacent DNA-binding domains and target DNA substrates. Several cancer-causing viruses encode viral bZIP TFs, including human T-cell leukemia virus (HTLV), hepatitis C virus (HCV) and the herpesviruses Marek’s disease virus (MDV), Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Here, we provide a comprehensive review of these viral bZIP TFs and their impact on viral replication, host cell responses and cell fate. Full article
(This article belongs to the Special Issue New Advances in Kaposi's Sarcoma-Associated Herpesvirus Research)
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