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. 2005 Apr 12;102(15):5570-5.
doi: 10.1073/pnas.0408192102. Epub 2005 Mar 30.

Kaposi's sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells

Xuezhong Cai  1 , Shihua Lu, Zhihong Zhang, Carlos M Gonzalez, Blossom Damania, Bryan R Cullen
Affiliations

Kaposi's sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells

Xuezhong Cai et al. Proc Natl Acad Sci U S A. .

Abstract

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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Figures

Fig. 1.
Fig. 1.
Predicted stem–loop structures of KSHV pri-miRNAs. These structural predictions were derived by using mfold (46). Mature miRNA sequences are highlighted.
Fig. 2.
Fig. 2.
Analysis of KSHV miRNA expression. (A) RT-PCR analysis performed using RNA samples derived from KSHV-infected BC-1 and BCBL-1 cells cultured under normal conditions or in the presence of TPA. ORF72 (v-cyclin) is a latent KSHV gene, and K12 is a latent gene that is activated during lytic replication, whereas ORF25 is strictly lytic. KSHV-negative BJAB cells served as a control. (B) Northern analysis of miR-K5 pre- and mature miRNA expression using a DNA probe perfectly complementary to mature miR-K5 (Table 2). The RNA samples used were the same as analyzed in A. Synthetic RNA markers (M) of 63 and 22 nt in length were run in parallel. (C) Similar to B, except that DNA probes complementary to the indicated viral miRNAs, a cellular miRNA (miR-16), or cellular U6 snRNA, were used.
Fig. 3.
Fig. 3.
Genomic location of the KSHV miRNAs. (Upper) A schematic of the 3′ end of the KSHV DNA genome with known ORFs, their orientation and expression pattern indicated. The KSHV miRNAs identified in this report are arrayed between ORF71 and K12, in noncoding sequences, with the exception of miR-K10, which overlaps the K12 ORF. White boxes, KSHV genes expressed during latent infection; gray boxes, KSHV genes expressed only during lytic infection; black boxes, KSHV pri-miRNA stem–loop precursors. The genomic orientation of each gene or miRNA is indicated by the arrow at the end of each box.
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