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Nucleophosmin Phosphorylation by v-Cyclin-CDK6 Controls KSHV Latency  [PDF]
Grzegorz Sarek,Annika J?rviluoma,Henna M. Moore,Sari Tojkander,Salla Vartia,Peter Biberfeld,Marikki Laiho equal contributor,P?ivi M. Ojala equal contributor
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000818
Abstract: Nucleophosmin (NPM) is a multifunctional nuclear phosphoprotein and a histone chaperone implicated in chromatin organization and transcription control. Oncogenic Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). In the infected host cell KSHV displays two modes of infection, the latency and productive viral replication phases, involving extensive viral DNA replication and gene expression. A sustained balance between latency and reactivation to the productive infection state is essential for viral persistence and KSHV pathogenesis. Our study demonstrates that the KSHV v-cyclin and cellular CDK6 kinase phosphorylate NPM on threonine 199 (Thr199) in de novo and naturally KSHV-infected cells and that NPM is phosphorylated to the same site in primary KS tumors. Furthermore, v-cyclin-mediated phosphorylation of NPM engages the interaction between NPM and the latency-associated nuclear antigen LANA, a KSHV-encoded repressor of viral lytic replication. Strikingly, depletion of NPM in PEL cells leads to viral reactivation, and production of new infectious virus particles. Moreover, the phosphorylation of NPM negatively correlates with the level of spontaneous viral reactivation in PEL cells. This work demonstrates that NPM is a critical regulator of KSHV latency via functional interactions with v-cyclin and LANA.
Herpesvirus of Turkeys (Meleagridis Herpesvirus 1) Encodes a Functional MicroRNA-221 Homolog with High Sequence Conservation  [PDF]
Yongxiu Yao, Chan Ding, Venugopal Nair
Advances in Microbiology (AiM) , 2019, DOI: 10.4236/aim.2019.98044
Abstract: Herpesviruses account for most of the known virus-encoded miRNAs. Herpesvirus of turkey (HVT), a non-pathogenic avian herpesvirus used as an avian vaccine and viral vector, encodes 28 mature miRNAs. This included HVT-miR-H14-3p that showed almost identical sequence to gga-miR-221, suggesting that it is pirated from the avian host. Although the functional homolog between the two miRNAs has been proposed based on the sequence similarity, the direct experimental evidence is still lacking. In this report, we provide the evidence for the first time that HVT-miR-H14-3p is indeed a gga-miR-221 homolog through modulating the expression of p27Kip1, a known target of miR-221 by binding to its 3’UTR. We also created an HVT-miR-H14-3p deletion virus and show that this miRNA is not essential for in vitro replication.
Mechanisms of Kaposi's Sarcoma-Associated Herpesvirus Latency and Reactivation  [PDF]
Fengchun Ye,Xiufen Lei,Shou-Jiang Gao
Advances in Virology , 2011, DOI: 10.1155/2011/193860
Abstract: The life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases. During latent infection, only a limited number of KSHV genes are expressed. However, this phase of replication is essential for persistent infection, evasion of host immune response, and induction of KSHV-related malignancies. KSHV reactivation from latency produces a wide range of viral products and infectious virions. The resulting de novo infection and viral lytic products modulate diverse cellular pathways and stromal microenvironment, which promote the development of Kaposi's sarcoma (KS). The mechanisms controlling KSHV latency and reactivation are complex, involving both viral and host factors, and are modulated by diverse environmental factors. Here, we review the cellular and molecular basis of KSHV latency and reactivation with a focus on the most recent advancements in the field. 1. Introduction Kaposi’s sarcoma-associated herpesvirus (KSHV) was identified in an acquired immune deficiency syndrome (AIDS) patient with Kaposi’s sarcoma (KS) [1]. Extensive studies have shown that KSHV is etiologically associated with KS, a vascular malignancy of endothelial cell origin, mostly involving the skin, oral cavity, and/or other subcutaneous tissues [2]. Clinical features of KS lesions include proliferation of KSHV latent nuclear antigen- (LANA- or LNA-) positive spindle-shaped tumor cells, extensive “slit-like” vascular networks, and infiltration of various inflammatory cells and red blood cells [3]. There are four clinical forms of KS: (1) classical KS, which is mainly seen in elderly men of Mediterranean and Eastern European origins, (2) endemic KS in Africa, (3) epidemic AIDS-related KS (AIDS-KS), and (4) iatrogenic KS in patients undergoing organ transplantation-related immunosuppression regimens. In Western countries, AIDS-KS is the most prevalent form of KS, which is also the most common malignancy in HIV patients [3]. KSHV is etiologically associated with all forms of KS. In addition to KS, KSHV is also causally implicated in several non-Hodgkin lymphomas including primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [4–6]. Like all herpesviruses, the life cycle of KSHV consists of latent and lytic replication phases [7]. In immunocompetent individuals, KSHV establishes latent infection following an acute infection. During latent infection, KSHV genome persists as a circular double-stranded DNA molecule (episome) in the nucleus with most viral genes being silenced except a few viral latent genes located in the
An In Vitro System for Studying Murid Herpesvirus-4 Latency and Reactivation  [PDF]
Janet S. May,Neil J. Bennett,Philip G. Stevenson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011080
Abstract: The narrow species tropisms of Epstein-Barr Virus (EBV) and the Kaposi's Sarcoma -associated Herpesvirus (KSHV) have made Murid Herpesvirus-4 (MuHV-4) an important tool for understanding how gammaherpesviruses colonize their hosts. However, while MuHV-4 pathogenesis studies can assign a quantitative importance to individual genes, the complexity of in vivo infection can make the underlying mechanisms hard to discern. Furthermore, the lack of good in vitro MuHV-4 latency/reactivation systems with which to dissect mechanisms at the cellular level has made some parallels with EBV and KSHV hard to draw. Here we achieved control of the MuHV-4 lytic/latent switch in vitro by modifying the 5′ untranslated region of its major lytic transactivator gene, ORF50. We terminated normal ORF50 transcripts by inserting a polyadenylation signal and transcribed ORF50 instead from a down-stream, doxycycline-inducible promoter. In this way we could establish fibroblast clones that maintained latent MuHV-4 episomes without detectable lytic replication. Productive virus reactivation was then induced with doxycycline. We used this system to show that the MuHV-4 K3 gene plays a significant role in protecting reactivating cells against CD8+ T cell recognition.
Antibody-Independent Control of γ-Herpesvirus Latency via B Cell Induction of Anti-Viral T Cell Responses  [PDF]
Kelly B McClellan,Shivaprakash Gangappa,Samuel H Speck,Herbert W. Virgin IV
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020058
Abstract: B cells can use antibody-dependent mechanisms to control latent viral infections. It is unknown whether this represents the sole function of B cells during chronic viral infection. We report here that hen egg lysozyme (HEL)-specific B cells can contribute to the control of murine γ-herpesvirus 68 (γHV68) latency without producing anti-viral antibody. HEL-specific B cells normalized defects in T cell numbers and proliferation observed in B cell?/? mice during the early phase of γHV68 latency. HEL-specific B cells also reversed defects in CD8 and CD4 T cell cytokine production observed in B cell?/? mice, generating CD8 and CD4 T cells necessary for control of latency. Furthermore, HEL-specific B cells were able to present virally encoded antigen to CD8 T cells. Therefore, B cells have antibody independent functions, including antigen presentation, that are important for control of γ-herpesvirus latency. Exploitation of this property of B cells may allow enhanced vaccine responses to chronic virus infection.
Cyclin-Dependent Kinase-Like Function Is Shared by the Beta- and Gamma- Subset of the Conserved Herpesvirus Protein Kinases  [PDF]
Chad V. Kuny,Karen Chinchilla,Michael R. Culbertson,Robert F. Kalejta
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001092
Abstract: The UL97 protein of human cytomegalovirus (HCMV, or HHV-5 (human herpesvirus 5)), is a kinase that phosphorylates the cellular retinoblastoma (Rb) tumor suppressor and lamin A/C proteins that are also substrates of cellular cyclin-dependent kinases (Cdks). A functional complementation assay has further shown that UL97 has authentic Cdk-like activity. The other seven human herpesviruses each encode a kinase with sequence and positional homology to UL97. These UL97-homologous proteins have been termed the conserved herpesvirus protein kinases (CHPKs) to distinguish them from other human herpesvirus-encoded kinases. To determine if the Cdk-like activities of UL97 were shared by all of the CHPKs, we individually expressed epitope-tagged alleles of each protein in human Saos-2 cells to test for Rb phosphorylation, human U-2 OS cells to monitor nuclear lamina disruption and lamin A phosphorylation, or S. cerevisiae cdc28-13 mutant cells to directly assay for Cdk function. We found that the ability to phosphorylate Rb and lamin A, and to disrupt the nuclear lamina, was shared by all CHPKs from the beta- and gamma-herpesvirus families, but not by their alpha-herpesvirus homologs. Similarly, all but one of the beta and gamma CHPKs displayed bona fide Cdk activity in S. cerevisiae, while the alpha proteins did not. Thus, we have identified novel virally-encoded Cdk-like kinases, a nomenclature we abbreviate as v-Cdks. Interestingly, we found that other, non-Cdk-related activities reported for UL97 (dispersion of promyelocytic leukemia protein nuclear bodies (PML-NBs) and disruption of cytoplasmic or nuclear aggresomes) showed weak conservation among the CHPKs that, in general, did not segregate to specific viral families. Therefore, the genomic and evolutionary conservation of these kinases has not been fully maintained at the functional level. Our data indicate that these related kinases, some of which are targets of approved or developmental antiviral drugs, are likely to serve both overlapping and non-overlapping functions during viral infections.
Kaposi’s Sarcoma-Associated Herpesvirus Genome Replication, Partitioning, and Maintenance in Latency  [PDF]
Keiji Ueda
Frontiers in Microbiology , 2012, DOI: 10.3389/fmicb.2012.00007
Abstract: Kaposi’s sarcoma-associated herpesvirus (KSHV) is thought to be an oncogenic member of the γ-herpesvirus subfamily. The virus usually establishes latency upon infection as a default infection pattern. The viral genome replicates according to the host cell cycle by recruiting the host cellular replication machinery. Among the latently expressing viral factors, LANA plays pivotal roles in viral genome replication, partitioning, and maintenance. LANA binds with two LANA-binding sites (LBS1/2) within a terminal repeat (TR) sequence and is indispensable for viral genome replication in latency. The nuclear matrix region seems to be important as a replication site, since LANA as well as cellular replication factors accumulate there and recruit the viral replication origin in latency (ori-P) by its binding activity to LBS. KSHV ori-P consists of LBS followed by a 32-bp GC-rich segment (32GC). Although it has been reported that LANA recruits cellular pre-replication complexes (pre-RC) such as origin recognition complexes (ORCs) to the ori-P through its interaction with ORCs, this mechanism does not account completely for the requirement of the 32GC. On the other hand, there are few reports about the partitioning and maintenance of the viral genome. LANA interacts with many kinds of chromosomal proteins, including Brd2/RING3, core histones, such as H2A/H2B and histone H1, and so on. The detailed molecular mechanisms by which LANA enables KSHV genome partitioning and maintenance still remain obscure. By integrating the findings reported thus far on KSHV genome replication, partitioning, and maintenance in latency, we will summarize what we know now, discuss what questions remain to be answered, and determine what needs to be done next to understand the mechanisms underlying viral replication, partitioning, and maintenance strategy.
Reactive Oxygen Species Hydrogen Peroxide Mediates Kaposi's Sarcoma-Associated Herpesvirus Reactivation from Latency  [PDF]
Fengchun Ye,Fuchun Zhou,Roble G. Bedolla,Tiffany Jones,Xiufen Lei,Tao Kang,Moraima Guadalupe,Shou-Jiang Gao
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002054
Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H2O2. Mechanistically, H2O2 induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H2O2 scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.
Intrabody-based Mapping of Latency-associated Nuclear Antigen from Kaposi’s Sarcoma-associated Herpesvirus Show Conserved Epitopes for Viral Latency Inhibition
Sofia Corte-Real, Lídia Fonseca, Carlos Barbas III and Joao Goncalves
Virology: Research and Treatment , 2012, DOI: 10.4137/VRT.S975
Abstract: Kaposi’s sarcoma associated herpesvirus (KSHV or human herpesvirus 8 [HHV-8]) is a gammaherpesvirus highly associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman’s disease, an aggressive lymphoproliferative disorder. KSHV, like other gammaherpesvirus latently infects predominantly B-cells and endothelial cells. Infected cells retain the virus from one generation to the next existing as a multicopy circular episomal DNA in the nucleus, expressing a limited subset of viral genes. Of these latently expressed genes, LANA1, the latency associated nuclear antigen is highly expressed in all forms of KS-associated malignancies. Various studies so far show that LANA1 tethers the viral episomes to host chromosomes and binds to specific sites within and close to the TR elements contributing to the stable maintenance of the viral episomes in successive daughter cells. Anti-LANA1 intrabody strategies might represent a new therapeutic approach to treatment of KSHV infections, since LANA1 is regained for KSHV latency. In addition, the use of intrabodies can help drug development by mapping LANA1 inhibiting regions. We report development of several LANA1 specific single chain antibodies from immunized rabbits that can be expressed intracellularly, bind to LANA1 epitopes and can be used for functional KSHV studies on viral latency.
Intrabody-based Mapping of Latency-associated Nuclear Antigen from Kaposi’s Sarcoma-associated Herpesvirus Show Conserved Epitopes for Viral Latency Inhibition
Sofia Corte-Real,Lídia Fonseca,Carlos Barbas III,Joao Goncalves
Virology: Research and Treatment , 2010,
Abstract: Kaposi’s sarcoma associated herpesvirus (KSHV or human herpesvirus 8 [HHV-8]) is a gammaherpesvirus highly associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman’s disease, an aggressive lymphoproliferative disorder. KSHV, like other gammaherpesvirus latently infects predominantly B-cells and endothelial cells. Infected cells retain the virus from one generation to the next existing as a multicopy circular episomal DNA in the nucleus, expressing a limited subset of viral genes. Of these latently expressed genes, LANA1, the latency associated nuclear antigen is highly expressed in all forms of KS-associated malignancies. Various studies so far show that LANA1 tethers the viral episomes to host chromosomes and binds to specific sites within and close to the TR elements contributing to the stable maintenance of the viral episomes in successive daughter cells. Anti-LANA1 intrabody strategies might represent a new therapeutic approach to treatment of KSHV infections, since LANA1 is regained for KSHV latency. In addition, the use of intrabodies can help drug development by mapping LANA1 inhibiting regions. We report development of several LANA1 specific single chain antibodies from immunized rabbits that can be expressed intracellularly, bind to LANA1 epitopes and can be used for functional KSHV studies on viral latency.
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