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 (nc) 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-gamma, 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 gamma-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 gamma-herpesviruses have evolved diverse strategies to converge on common targets in host T cells.