Cloning and Identification of a MicroRNA Cluster within the Latency-Associated Region of Kaposi's Sarcoma-Associated Herpesvirus

Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
Journal of Virology (Impact Factor: 4.44). 08/2005; 79(14):9301-5. DOI: 10.1128/JVI.79.14.9301-9305.2005
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MicroRNAs (miRNAs) are small, noncoding regulatory RNA molecules that bind to 3' untranslated regions (UTRs) of mRNAs to either prevent their translation or induce their degradation. Previously identified in a variety of organisms ranging from plants to mammals, miRNAs are also now known to be produced by viruses. The human gammaherpesvirus Epstein-Barr virus has been shown to encode miRNAs, which potentially regulate both viral and cellular genes. To determine whether Kaposi's sarcoma-associated herpesvirus (KSHV) encodes miRNAs, we cloned small RNAs from KSHV-positive primary effusion lymphoma-derived cells and endothelial cells. Sequence analysis revealed 11 isolated RNAs of 19 to 23 bases in length that perfectly align with KSHV. Surprisingly, all candidate miRNAs mapped to a single genomic locale within the latency-associated region of KSHV. These data suggest that viral and host cellular gene expression may be regulated by miRNAs during both latent and lytic KSHV replication.

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Available from: Rebecca L Skalsky, Sep 30, 2015
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    • "However, it has yet to be revealed if LANA1 functions in this manner in DC. HHV-8 also produces multiple microRNAs, all of which are encoded within latency-associated genes (Samols et al., 2005), and are detectable in latently infected B cell lines suggesting that they play a role in inducing and/or maintenance of HHV-8 latency (Cai et al., 2005). However, their impact on DC function is not clear and could be studied with RNA silencing technology. "
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    ABSTRACT: Human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) is an oncogenic gammaherpesvirus that primarily infects cells of the immune and vascular systems. HHV-8 interacts with and targets professional antigen presenting cells and influences their function. Infection alters the maturation, antigen presentation, and immune activation capabilities of certain dendritic cells (DC) despite non-robust lytic replication in these cells. DC sustains a low level of antiviral functionality during HHV-8 infection in vitro. This may explain the ability of healthy individuals to effectively control this virus without disease. Following an immune compromising event, such as organ transplantation or human immunodeficiency virus type 1 infection, a reduced cellular antiviral response against HHV-8 compounded with skewed DC cytokine production and antigen presentation likely contributes to the development of HHV-8 associated diseases, i.e., Kaposi's sarcoma and certain B cell lymphomas. In this review we focus on the role of DC in the establishment of HHV-8 primary and latent infection, the functional state of DC during HHV-8 infection, and the current understanding of the factors influencing virus-DC interactions in the context of HHV-8-associated disease.
    Frontiers in Microbiology 08/2014; 5:452. DOI:10.3389/fmicb.2014.00452 · 3.99 Impact Factor
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    • "One possible mechanism for inducing viral lytic genes is through repression of KSHV-encoded microRNAs (miRNAs). Thus far, 12 KSHV pre-miRNAs, encoding 18 mature miRNAs have been identified [23]–[25]. Recent published data demonstrate a role for KSHV miRNAs including miR-K12-1, 3, 4, 5, 9 and 11, in the regulation of viral “latent-lytic switch” in KSHV-infected cells (mostly for maintaining viral latency in host cells), through either direct targeting viral lytic reactivation activator, RTA [26], [27], or indirect mechanisms including targeting varied host factors including IκBα, nuclear factor I/B (NFIB) and IKKε [28]–[30]. Therefore, we sought to determine whether higher expressional levels of lytic genes in ascites cells were due to changes in the viral miRNA profile. "
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    ABSTRACT: Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), which arises preferentially in the setting of infection with human immunodeficiency virus (HIV). Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+) PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV(+) PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID) mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.
    PLoS ONE 02/2014; 9(2):e90349. DOI:10.1371/journal.pone.0090349 · 3.23 Impact Factor
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    • "Epstein–Barr virus (EBV) 25 miRNA expression from two clusters: 3 BHRF1 miRNA hairpins, which are expressed only during latency III, and 22 BART miRNA hairpins (Pfeffer et al. 2004; Cai et al. 2006; Zhu et al. 2009). The BHRF1 miRNAs promote B cell immortalization by EBV (Seto et al. 2010; Feederle et al. 2011a; Feederle et al. 2011b) Kaposi's sarcoma– associated herpesvirus (KSHV) 12 miRNA expression from one cluster during latency (Cai et al. 2005; Pfeffer et al. 2005; Samols et al. 2005; Grundhoff et al. 2006). miR- K11 is a viral mimic of cellular miR-155 (Gottwein et al. 2007; Skalsky et al. 2007) a Herpesvirus saimiri (HVS) 3 pre-miRNAs are excised by the integrator complex (Cazalla et al. 2011) a Murine γ-herpesvirus 68 (MHV68) 15 pri-miRNAs driven by Pol III, pre-miRNAs excised by tRNaseZ (Pfeffer et al. 2005; Bogerd et al. 2010) If retroviruses were to express Drosha-dependent miRNAs from the viral LTR promoter , this would result in at least partial degradation of the viral genome. "
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    ABSTRACT: MicroRNAs (miRNAs) are a class of small noncoding RNAs expressed by plants, animals, and some viruses. miRNAs generally function as part of miRNA-induced silencing complexes to modestly repress mRNAs with imperfect sequence complementarity. Over the last years, many different roles of miRNA mediated regulation in the life cycles of mammalian viruses have been uncovered. In this chapter, I will mainly explore four different examples of how cellular miRNAs interact with viruses: the role of miR-155 in viral oncogenesis, viral strategies to eliminate cellular miR-27, the contribution of miR-122 to the replication of hepatitis C virus, and miRNAs as an experimental tool to control virus replication and vector transgene expression. In the final part of this chapter, I will give a brief overview of virally encoded microRNAs.
    Current topics in microbiology and immunology 05/2013; 371:201-227. DOI:10.1007/978-3-642-37765-5_8 · 4.10 Impact Factor
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