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

Abstract

SUMMARY 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.

Excessive expression of miR-27 impairs Treg-mediated immunological tolerance

“…Five months after birth, these mice started to develop autoimmune disorders that manifested in runting, failure to thrive, lymphadenopathy and splenomegaly, and lymphocytic tissue infiltration that was particularly severe in the lung, colon, and stomach (Supplemental Figure 1B and data not shown). Interestingly, regardless of the absence or presence of increased IFN-γ + T cell frequencies in younger or older CD4-Cre R27Tg mice, respectively ( Figure 1, A and B), we could consistently detect reduced IFN-γ production by miR-27-overexpressing T cells on a per-cell basis ( Figure 1C), supporting the previous notion that miR-27 functions as a potent repressor of IFN-γ in T cells (13,14).…”

“…Moreover, our recent finding of elevated IFN-γ responses and lympho-hyperactivated phenotypes in mice harboring T cells with miR-27 overexpression further supported the conclusion drawn by the aforementioned study in patients with MS (11,12). Surprisingly, the role of miR-27 in driving IFN-γ-mediated Th1 autoimmune responses implicated by these 2 reports seems to be at odds with previous studies, in which miR-27 was shown to be a potent repressor of IFN-γ and T cell receptor-mediated (TCR-mediated) activation (13,14). The fact that overexpression of miR-27 in T cells resulted in impaired Th1 differentiation further suggested that miR-27-mediated gene regulation limits, rather than promotes, Th1 responses (12).…”

“…Previously, it has been shown that miR-27 could attenuate T cell responses through direct targeting of IFN-γ (13,14). Therefore, it was initially puzzling to find dysregulated IFN-γ responses in both patients with MS and mice harboring T cells with excessive miR-27 expression (11,12).…”

RNA-mediated degradation of microRNAs: A widespread viral strategy?

“…44 HSUR-1 in HVS may be a little older. A homologous site within the same type of RNA element (HAUR-1) is found in a closely related rhadinovirus from spider monkeys, Herpesvirus ateles (HVA), 45 but not in other rhadinoviruses infecting Old World monkeys and apes. Squirrel monkeys and spider monkeys are both New world monkeys, and are thought to have shared a common ancestor around 20 Myr ago.…”

“…First, has miR-27 always played an antiviral role? In the case of HVS infection of T cells, Guo et al identified and validated miR-27 targets that are involved in T cell receptor (TCR) signaling, 45 a pathway which is activated in HVS-transformed human T cells. 47 While this particular pathway is unlikely to be relevant to MCMV, which does not infect T cells, it was also shown that miR-27 suppressed mitogen-activated protein kinase (MAPK) signaling and effector cytokines (IFN-g, IL-10) that are part of the cellular response to many viruses including MCMV.…”