Alternative Capture of Noncoding RNAs or Protein-Coding Genes by Herpesviruses to Alter Host T-Cell Function

In marmoset T cells transformed by Herpesvirus saimiri (HVS), a viral U-rich noncoding RNA, HSUR 1, specifically mediates degradation of host microRNA-27 (miR-27). High-throughput sequencing of RNA after crosslinking immunoprecipitation (HITS-CLIP) identified mRNAs targeted by miR-27 as enriched in the T-cell receptor (TCR) signaling pathway, including GRB2. Accordingly, transfection of miR-27 into human T cells attenuates TCR-induced activation of mitogen-activated protein kinases (MAPKs) and induction of CD69. MiR-27 also robustly regulates SEMA7A and IFN-γ, key modulators and effectors of T-cell function. Knockdown or ectopic expression of HSUR 1 alters levels of these proteins in virally-transformed cells. Two other T-lymphotropic γ-herpesviruses, AlHV-1 and OvHV-2, do not produce a noncoding RNA to downregulate miR-27, but instead encode homologs of miR-27 target genes. Thus, oncogenic γ-herpesviruses have evolved diverse strategies to converge on common targets in host T cells. HVS-transformed marmoset T cells were transfected with ASOs against HSUR 1 or control, or with LNAs against miR-27 or control, in replicates; poly A+ RNAs were selected and sequenced on HiSeq 2000.