Cai X, Lu S, Zhang Z, Gonzalez CM, Damania B, Cullen BRKaposi's sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Natl Acad Sci USA 102: 5570-5575

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2005; 102(15):5570-5. DOI: 10.1073/pnas.0408192102
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MicroRNAs (miRNAs) are an endogenously encoded class of small RNAs that have been proposed to function as key posttranscriptional regulators of gene expression in a range of eukaryotic species, including humans. The small size of miRNA precursors makes them potentially ideal for use by viruses as inhibitors of host cell defense pathways. Here, we demonstrate that the pathogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) encodes an array of 11 distinct miRNAs, all of which are expressed at readily detectable levels in latently KSHV infected cells. Individual KSHV miRNAs were expressed at up to 2,200 copies per cell. The KSHV miRNAs are expressed from what appears to be a single genetic locus that largely coincides with an approximately 4-kb noncoding sequence located between the KSHV v-cyclin and K12/Kaposin genes, both of which are also expressed in latently infected cells. Computer analysis of potential mRNA targets for these viral miRNAs identified a number of interesting candidate genes, including several mRNAs previously shown to be down-regulated in KSHV-infected cells. We hypothesize that these viral miRNAs play a critical role in the establishment and/or maintenance of KSHV latent infection in vivo and, hence, in KSHV-induced oncogenesis.

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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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    • "MiR-BART2 encoded by EBV inhibits the lytic viral gene BALF5 and thus may play an important role in maintenance of EBV latency [9]. Similarly, KSHV-encoded miR-9 inhibits expression of the viral protein RTA and miR-K1 targets IκBα to activate the NF-κB pathway, which in turn prevents lytic infection of KSHV and promotes latency [10], [11]. Viral miRNAs also regulate host immune responses and mediate viral immune evasion. "
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    ABSTRACT: Human cytomegalovirus (HCMV) encodes microRNAs (miRNAs) that function as post-transcriptional regulators of gene expression during lytic infection in permissive cells. Some miRNAs have been shown to suppress virus replication, which could help HCMV to establish or maintain latent infection. However, HCMV miRNA expression has not been comprehensively examined and compared using cell culture systems representing permissive (lytic) and semi-permissive vs. non-permissive (latent-like) infection. Viral miRNAs levels and expression kinetics during HCMV infection were determined by miRNA-specific stem-loop RT-PCR. HCMV infected THP-1 (non-permissive), differentiated THP-1 (d-THP-1, semi-permissive) and human embryo lung fibroblasts (HELs, fully-permissive) were examined. The impact of selected miRNAs on HCMV infection (gene expression, genome replication and virus release) was determined by Western blotting, RT-PCR, qPCR, and plaque assay. Abundant expression of 15 HCMV miRNAs was observed during lytic infection in HELs; highest peak inductions (11- to 1502-fold) occurred at 48 hpi. In d-THP-1s, fourteen mRNAs were detected with moderate induction (3- to 288-fold), but kinetics of expression was generally delayed for 24 h relative to HELs. In contrast, only three miRNAs were induced to low levels (3- to 4-fold) during quiescent infection in THP-1s. Interestingly, miR-UL70-3p was poorly induced in HEL (1.5-fold), moderately in THP-1s (4-fold), and strongly (58-fold) in d-THP-1s, suggesting a potentially specific role for miR-UL70-3p in THP-1s and d-THP-1s. MiR-US33, -UL22A and -UL70 were further evaluated for their impact on HCMV replication in HELs. Ectopic expression of miR-UL22A and miR-UL70 did not affect HCMV replication in HELs, whereas miR-US33 inhibited HCMV replication and reduced levels of HCMV US29 mRNA, confirming that US29 is a target of miR-US33. Viral miRNA expression kinetics differs between permissive, semi-permissive and quiescent infections, and miR-US33 down-regulates HCMV replication. These results suggest that miR-US33 may function to impair entry into lytic replication and hence promote establishment of latency.
    PLoS ONE 02/2014; 9(2):e88531. DOI:10.1371/journal.pone.0088531 · 3.23 Impact Factor
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    • "An increased proportion of virus-encoded miRNAs to host-encoded miRNAs is not uncommon in transformed cell lines. For example, miRNAs encoded by Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus (EBV) accounted for ∼40% of the entire miRNA pool identified from the BC-1 cell line coinfected with these two viruses (52). The total proportion of virus-encoded miRNAs of Marek's disease virus type 1 (MDV-1) and Marek's disease virus type 2 (MDV-2) in an MSB-1 cell library was 61% (53). "
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    ABSTRACT: To date, the vast majority of known virus-encoded microRNAs (miRNAs) are derived from polymerase II transcripts encoded by DNA viruses. A recent demonstration that the bovine leukemia virus, a retrovirus, uses RNA polymerase III to directly transcribe the pre-miRNA hairpins to generate viral miRNAs further supports the common notion that the canonical pathway of miRNA biogenesis does not exist commonly among RNA viruses. Here, we show that an exogenous virus-specific region, termed the E element or XSR, of avian leukosis virus subgroup J (ALV-J), a member of avian retrovirus, encodes a novel miRNA, designated E (XSR) miRNA, using the canonical miRNA biogenesis pathway. Detection of novel microRNA species derived from the E (XSR) element, a 148-nucleotide noncoding RNA with hairpin structure, showed that the E (XSR) element has the potential to function as a microRNA primary transcript, demonstrating a hitherto unknown function with possible roles in myeloid leukosis associated with ALV-J.
    Journal of Virology 10/2013; 88(1). DOI:10.1128/JVI.02921-13 · 4.44 Impact Factor
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