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19 pages, 5768 KiB

Open AccessArticle

Nucleolin Regulates the Expression of Kaposi’s Sarcoma-Associated Herpesvirus’ Latency-Associated Nuclear Antigen through G-Quadruplexes in the mRNA

by Andrew R. Zareie and Subhash C. Verma

Viruses 2023, 15(12), 2438; https://doi.org/10.3390/v15122438 - 15 Dec 2023

Cited by 1 | Viewed by 885

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes life-long latent infection and is linked to several human malignancies. Latency-associated nuclear antigen (LANA) is highly expressed during latency, and is responsible for the replication and maintenance of the viral genome. The expression of LANA is regulated at [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes life-long latent infection and is linked to several human malignancies. Latency-associated nuclear antigen (LANA) is highly expressed during latency, and is responsible for the replication and maintenance of the viral genome. The expression of LANA is regulated at transcriptional/translational levels through multiple mechanisms, including the secondary structures in the mRNA sequence. LANA mRNA has multiple G-quadruplexes (G4s) that are bound by multiple proteins to stabilize/destabilize these secondary structures for regulating LANA. In this manuscript, we demonstrate the role of Nucleolin (NCL) in regulating LANA expression through its interaction with G-quadruplexes of LANA mRNA. This interaction reduced LANA’s protein expression through the sequestration of mRNA into the nucleus, demonstrated by the colocalization of G4-carrying mRNA with NCL. Furthermore, the downregulation of NCL, by way of a short hairpin, showed an increase in LANA translation following an alteration in the levels of LANA mRNA in the cytoplasm. Overall, the data presented in this manuscript showed that G-quadruplexes-mediated translational control could be regulated by NCL, which can be exploited for controlling KSHV latency. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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21 pages, 6011 KiB

Open AccessArticle

m⁶A Regulates the Stability of Cellular Transcripts Required for Efficient KSHV Lytic Replication

by Oliver Manners, Belinda Baquero-Perez, Timothy J. Mottram, Ivaylo D. Yonchev, Christopher J. Trevelyan, Katherine L. Harper, Sarah Menezes, Molly R. Patterson, Andrew Macdonald, Stuart A. Wilson, Julie L. Aspden and Adrian Whitehouse

Viruses 2023, 15(6), 1381; https://doi.org/10.3390/v15061381 - 16 Jun 2023

Cited by 1 | Viewed by 1452

Abstract

The epitranscriptomic modification N⁶-methyladenosine (m⁶A) is a ubiquitous feature of the mammalian transcriptome. It modulates mRNA fate and dynamics to exert regulatory control over numerous cellular processes and disease pathways, including viral infection. Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation from [...] Read more.

The epitranscriptomic modification N⁶-methyladenosine (m⁶A) is a ubiquitous feature of the mammalian transcriptome. It modulates mRNA fate and dynamics to exert regulatory control over numerous cellular processes and disease pathways, including viral infection. Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation from the latent phase leads to the redistribution of m⁶A topology upon both viral and cellular mRNAs within infected cells. Here we investigate the role of m⁶A in cellular transcripts upregulated during KSHV lytic replication. Our results show that m⁶A is crucial for the stability of the GPRC5A mRNA, whose expression is induced by the KSHV latent–lytic switch master regulator, the replication and transcription activator (RTA) protein. Moreover, we demonstrate that GPRC5A is essential for efficient KSHV lytic replication by directly regulating NFκB signalling. Overall, this work highlights the central importance of m⁶A in modulating cellular gene expression to influence viral infection. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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18 pages, 3753 KiB

Open AccessArticle

The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection

by Cassandra M. Bonavita, Timothy M. White, Joseph Francis, Helen E. Farrell, Nicholas J. Davis-Poynter and Rhonda D. Cardin

Viruses 2023, 15(3), 711; https://doi.org/10.3390/v15030711 - 09 Mar 2023

Cited by 1 | Viewed by 1351

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects the majority of the world population and causes lifelong latent infection. HCMV has been shown to exacerbate cardiovascular diseases, including myocarditis, vascular sclerosis, and transplant vasculopathy. Recently, we have shown that murine CMV (MCMV) [...] Read more.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects the majority of the world population and causes lifelong latent infection. HCMV has been shown to exacerbate cardiovascular diseases, including myocarditis, vascular sclerosis, and transplant vasculopathy. Recently, we have shown that murine CMV (MCMV) recapitulates the cardiovascular dysfunction observed in patients with HCMV-induced myocarditis. To understand the viral mechanisms involved in CMV-induced heart dysfunction, we further characterized cardiac function in response to MCMV and examined virally encoded G-protein-coupled receptor homologs (vGPCRs) US28 and M33 as potential factors that promote infection in the heart. We hypothesized that the CMV-encoded vGPCRs could exacerbate cardiovascular damage and dysfunction. Three viruses were used to evaluate the role of vGPCRs in cardiac dysfunction: wild-type MCMV, a M33-deficient virus (∆M33), and a virus with the M33 open reading frame (ORF) replaced with US28, an HCMV vGPCR (i.e., US28+). Our in vivo studies revealed that M33 plays a role in promoting cardiac dysfunction by increasing viral load and heart rate during acute infection. During latency, ΔM33-infected mice demonstrated reduced calcification, altered cellular gene expression, and less cardiac hypertrophy compared with wild-type MCMV-infected mice. Ex vivo viral reactivation from hearts was less efficient in ΔM33-infected animals. HCMV protein US28 expression restored the ability of the M33-deficient virus to reactivate from the heart. US28+ MCMV infection caused damage to the heart comparable with wild-type MCMV infection, suggesting that the US28 protein is sufficient to complement the function of M33 in the heart. Altogether, these data suggest a role for vGPCRs in viral pathogenesis in the heart and thus suggest that vGPCRs promote long-term cardiac damage and dysfunction. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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14 pages, 5004 KiB

Open AccessArticle

Inactivation of the UL37 Deamidase Enhances Virus Replication and Spread of the HSV-1(VC2) Oncolytic Vaccine Strain and Secretion of GM-CSF

by Carolyn M. Clark, Nithya Jambunathan, Therese M. A. Collantes and Konstantin G. Kousoulas

Viruses 2023, 15(2), 367; https://doi.org/10.3390/v15020367 - 27 Jan 2023

Cited by 1 | Viewed by 1730

Abstract

The HSV-1 (VC2) live-attenuated vaccine strain was engineered with specific deletions in the amino termini of glycoprotein K (gK) and membrane protein UL20, rendering the virus unable to enter neurons and establish latency. VC2 replicates efficiently in epithelial cell culture but produces lower [...] Read more.

The HSV-1 (VC2) live-attenuated vaccine strain was engineered with specific deletions in the amino termini of glycoprotein K (gK) and membrane protein UL20, rendering the virus unable to enter neurons and establish latency. VC2 replicates efficiently in epithelial cell culture but produces lower viral titers and smaller viral plaques than its parental HSV-1 (F) wild-type virus. VC2 is an effective live-attenuated vaccine against HSV-1 and HSV-2 infections in mice and guinea pigs and an anti-tumor immunotherapeutic and oncolytic virus against melanoma and breast cancer in mouse models. Previously, we reported that the gK/UL20 complex interacts with the UL37 tegument protein, and this interaction is essential for virion intracellular envelopment and egress. To investigate the potential role of the UL37 deamidase functions, the recombinant virus FC819S and VC2C819S were constructed with a C819S substitution to inactivate the UL37 predicted deamidase active site on an HSV-1(F) and HSV-1(VC2) genetic background, respectively. FC819S replicated to similar levels with HSV-1(F) and produced similar size viral plaques. In contrast, VC2C819S replication was enhanced, and viral plaques increased in size, approaching those of the wild-type HSV-1(F) virus. FC819S infection of cell cultures caused enhanced GM-CSF secretion in comparison to HSV-1(F) across several cell lines, including HEp2 cells and cancer cell lines, DU145 (prostate) and Panc 04.03 (pancreas), and primary mouse peritoneal cells. VC2 infection of these cell lines caused GM-CSF secretion at similar levels to FC819S infection. However, the VC2C819S virus did not exhibit any further enhancement of GM-CSF secretion compared to the VC2 virus. These results suggest that the UL37 deamidation functions in conjunction with the gK/UL20 complex to facilitate virus replication and GM-CSF secretion. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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20 pages, 2949 KiB

Open AccessArticle

DExD/H Box Helicases DDX24 and DDX49 Inhibit Reactivation of Kaposi’s Sarcoma Associated Herpesvirus by Interacting with Viral mRNAs

by Jacquelyn C. Serfecz, Yuan Hong, Lauren A. Gay, Ritu Shekhar, Peter C. Turner and Rolf Renne

Viruses 2022, 14(10), 2083; https://doi.org/10.3390/v14102083 - 20 Sep 2022

Cited by 1 | Viewed by 2026

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that is the causative agent of primary effusion lymphoma and Kaposi’s sarcoma. In healthy carriers, KSHV remains latent, but a compromised immune system can lead to lytic viral replication that increases the probability of tumorigenesis. [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that is the causative agent of primary effusion lymphoma and Kaposi’s sarcoma. In healthy carriers, KSHV remains latent, but a compromised immune system can lead to lytic viral replication that increases the probability of tumorigenesis. RIG-I-like receptors (RLRs) are members of the DExD/H box helicase family of RNA binding proteins that recognize KSHV to stimulate the immune system and prevent reactivation from latency. To determine if other DExD/H box helicases can affect KSHV lytic reactivation, we performed a knock-down screen that revealed DHX29-dependent activities appear to support viral replication but, in contrast, DDX24 and DDX49 have antiviral activity. When DDX24 or DDX49 are overexpressed in BCBL-1 cells, transcription of all lytic viral genes and genome replication were significantly reduced. RNA immunoprecipitation of tagged DDX24 and DDX49 followed by next-generation sequencing revealed that the helicases bind to mostly immediate-early and early KSHV mRNAs. Transfection of expression plasmids of candidate KSHV transcripts, identified from RNA pull-down, demonstrated that KSHV mRNAs stimulate type I interferon (alpha/beta) production and affect the expression of multiple interferon-stimulated genes. Our findings reveal that host DExD/H box helicases DDX24 and DDX49 recognize gammaherpesvirus transcripts and convey an antiviral effect in the context of lytic reactivation. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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30 pages, 8027 KiB

Open AccessArticle

Role of PARP-1 in Human Cytomegalovirus Infection and Functional Partners Encoded by This Virus

by Wenchang Zhang, Jing Guo and Qiang Chen

Viruses 2022, 14(9), 2049; https://doi.org/10.3390/v14092049 - 15 Sep 2022

Cited by 6 | Viewed by 1929

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that threats the majority of the world’s population. Poly (ADP-ribose) polymerase 1 (PARP-1) and protein poly (ADP-ribosyl)ation (PARylation) regulates manifold cellular functions. The role of PARP-1 and protein PARylation in HCMV infection is still unknown. In [...] Read more.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that threats the majority of the world’s population. Poly (ADP-ribose) polymerase 1 (PARP-1) and protein poly (ADP-ribosyl)ation (PARylation) regulates manifold cellular functions. The role of PARP-1 and protein PARylation in HCMV infection is still unknown. In the present study, we found that the pharmacological and genetic inhibition of PARP-1 attenuated HCMV replication, and PARG inhibition favors HCMV replication. PARP-1 and its enzymatic activity were required for efficient HCMV replication. HCMV infection triggered the activation of PARP-1 and induced the translocation of PARP-1 from nucleus to cytoplasm. PARG was upregulated in HCMV-infected cells and this upregulation was independent of viral DNA replication. Moreover, we found that HCMV UL76, a true late protein of HCMV, inhibited the overactivation of PARP-1 through direct binding to the BRCT domain of PARP-1. In addition, UL76 also physically interacted with poly (ADP-ribose) (PAR) polymers through the RG/RGG motifs of UL76 which mediates its recruitment to DNA damage sites. Finally, PARP-1 inhibition or depletion potentiated HCMV-triggered induction of type I interferons. Our results uncovered the critical role of PARP-1 and PARP-1-mediated protein PARylation in HCMV replication. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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18 pages, 3492 KiB

Open AccessArticle

Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro

by Mathilde Bergamelli, Hélène Martin, Yann Aubert, Jean-Michel Mansuy, Marlène Marcellin, Odile Burlet-Schiltz, Ilse Hurbain, Graça Raposo, Jacques Izopet, Thierry Fournier, Alexandra Benchoua, Mélinda Bénard, Marion Groussolles, Géraldine Cartron, Yann Tanguy Le Gac, Nathalie Moinard, Gisela D’Angelo and Cécile E. Malnou

Viruses 2022, 14(9), 2030; https://doi.org/10.3390/v14092030 - 13 Sep 2022

Cited by 5 | Viewed by 3048

Abstract

Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on [...] Read more.

Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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Review

Jump to: Research

15 pages, 3417 KiB

Open AccessReview

Cellular Processes Induced by HSV-1 Infections in Vestibular Neuritis

by Zhengdong Zhao, Xiaozhou Liu, Yanjun Zong, Xinyu Shi and Yu Sun

Viruses 2024, 16(1), 12; https://doi.org/10.3390/v16010012 - 20 Dec 2023

Viewed by 1137

Abstract

Herpesvirus is a prevalent pathogen that primarily infects human epithelial cells and has the ability to reside in neurons. In the field of otolaryngology, herpesvirus infection primarily leads to hearing loss and vestibular neuritis and is considered the primary hypothesis regarding the pathogenesis [...] Read more.

Herpesvirus is a prevalent pathogen that primarily infects human epithelial cells and has the ability to reside in neurons. In the field of otolaryngology, herpesvirus infection primarily leads to hearing loss and vestibular neuritis and is considered the primary hypothesis regarding the pathogenesis of vestibular neuritis. In this review, we provide a summary of the effects of the herpes virus on cellular processes in both host cells and immune cells, with a focus on HSV-1 as illustrative examples. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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19 pages, 2831 KiB

Open AccessReview

The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective

by Hemant Borase and Deepak Shukla

Viruses 2023, 15(11), 2195; https://doi.org/10.3390/v15112195 - 31 Oct 2023

Cited by 1 | Viewed by 1607

Abstract

Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular processes, from harnessing host machinery for replication to subverting antiviral defenses like autophagy and programmed cell death, exemplifies the intricate interplay [...] Read more.

Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular processes, from harnessing host machinery for replication to subverting antiviral defenses like autophagy and programmed cell death, exemplifies the intricate interplay at the heart of its pathogenesis. While the biomedical community has extensively researched antiviral interventions, the efficiency of these strategies in managing HSV-2 remains suboptimal. Recognizing this, attention has shifted toward leveraging host cellular components to regulate HSV-2 replication and influence the cell cycle. Furthermore, innovative interventional strategies—including drug repurposing, microbivacs, connecting the host microbiome, and exploiting natural secondary metabolites—are emerging as potential game changers. This review summarizes the key steps in HSV-2 pathogenesis and newly discovered cellular interactions, presenting the latest developments in the field, highlighting existing challenges, and offering a fresh perspective on HSV-2’s pathogenesis and the potential avenues for its treatment by targeting cellular proteins and pathways. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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15 pages, 566 KiB

Open AccessReview

RNA Editing-Dependent and -Independent Roles of Adenosine Deaminases Acting on RNA Proteins in Herpesvirus Infection—Hints on Another Layer of Complexity

by Vlatka Ivanišević, Lidia Žilić, Marina Čunko, Hana Fadiga, Ivana Munitić and Igor Jurak

Viruses 2023, 15(10), 2007; https://doi.org/10.3390/v15102007 - 27 Sep 2023

Viewed by 1083

Abstract

The Adenosine Deaminases Acting on RNA (ADAR) catalyze the posttranscriptional deamination of adenosine residues to inosine in double-stranded RNAs (dsRNAs, A-to-I editing), preventing the overactivation of dsRNA sensor molecules and interferons. RNA editing is the cornerstone of innate immunity that distinguishes between self [...] Read more.

The Adenosine Deaminases Acting on RNA (ADAR) catalyze the posttranscriptional deamination of adenosine residues to inosine in double-stranded RNAs (dsRNAs, A-to-I editing), preventing the overactivation of dsRNA sensor molecules and interferons. RNA editing is the cornerstone of innate immunity that distinguishes between self and non-self (virus), and it is essential for normal regulation of cellular homeostasis. Although much is already known about the role of ADAR proteins in RNA virus infection, the role of ADAR proteins in herpesvirus infection remains largely unexplored. In this review, we provide several lines of evidence from studies of different herpesviruses for another level of complexity in regulating the already intricate biphasic life cycle of herpesviruses. Full article

(This article belongs to the Special Issue Herpesvirus Manipulation of Cellular Processes 2.0)

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