A role for the Herpesvirus saimiri U RNAs in latently infected T cells

Herpesvirus saimiri (HVS), a gamma-Herpesvirus that causes aggressive T cell leukemias and lymphomas in New World primates, encodes seven small nuclear RNAs of the Sm class called HSURs, for H&barbelow;erpesvirus s&barbelow;aimiri U&barbelow; R&barbelow;NAs. The HSURs are abundantly expressed in T cells transformed by HVS both in vivo and in vitro.; HSURs 1, 2 and 5 have highly conserved 5' end AU-rich sequences containing the AUUUA pentamer characteristic of AU-rich elements (AREs) that regulate the stability of many host mRNAs, including those of most proto-oncogenes and cytokines, and have been proposed to alter the stability of these mRNAs by sequestering host proteins that regulate their decay. We show that the ARE-containing HSURs interact with the ARE-binding proteins hnRNP D and HuR in HVS-transformed T cells using a novel in vivo UV cross-linking assay and with TTP in activated T cells by in vitro UV cross-linking. Comprehensive Northern and microarray analyses revealed, however, that the absence of HSURs 1 and 2 does not alter the levels of endogenous ARE-containing mRNAs in latently infected T cells. Instead, HSUR 1 itself is degraded by an ARE-dependent pathway in HVS-transformed T cells, suggesting that HVS may take advantage of the host ARE-mediated mRNA decay pathway to regulate HSUR expression. This is the first example of post-transcriptional regulation of the expression of an Sm snRNA.; We further investigated HSUR function by an extensive comparison of host gene expression in common marmoset T cells transformed with wild-type HVS and a mutant HVS lacking HSURs 1 and 2 by both microarray and Northern analyses. We demonstrate that expression of the most highly conserved HSURs, HSURs 1 and 2, correlates with increased expression of T cell receptors and other T cell and natural killer (NK) cell surface receptors, including CD52 and DAP10. Intracellular genes linked to T cell and NK cell activation, including SKAP55, granulysin, and NKG7, were also upregulated in the presence of HSURs 1 and 2. These are the first phenotypic changes attributable to expression of the HSURs and suggest that the HSURs enhance the activation state of HVS-transformed T cells during latency.