Infection due to cytomegalovirus (CMV) remains an important cause of morbidity and mortality among persons with impaired cellular immunity, such as those undergoing stem cell or solid organ transplantation and individuals infected with HIV. The clinical manifestations of CMV infection among immunocompromised hosts are varied, ranging from asymptomatic viremia to encephalitis, pneumonitis, colitis, and myelosuppression. However, viral determinants of pathogenicity are poorly understood. During acute infection, CMV induces production of interferon (IFN) by CD4+ T cells, and this is a critical component of the host defense mechanism against viral infection. IFN exerts its antiviral effects through many mechanisms. One such pathway is the shut-off of host cellular protein synthesis via the up-regulation of cellular protein kinase R (PKR) and 2-5- oligoadenylate synthetase (2-50AS). These enzymes are dependent on the presence of viral double-stranded RNA (dsRNA) for activation. Many viruses encode proteins that bind to and sequester dsRNA, thereby allowing continued cellular protein synthesis and viral propagation. The importance of counteracting this pathway in viral pathogenesis has been demonstrated in vaccinia virus and herpes-simplex virus 1. Cellular protein synthesis continues in cells infected with human CMV (HCMV), although the mechanism by which this occurs is unclear. We hypothesize that HCMV encodes dsRNA-binding proteins that serve to counteract the IFN-induced shut-off of host cellular protein synthesis by inhibiting the PKR and 2-5 0AS pathways. We hypothesize that TRS1 is such a gene in HCMV. The dsRNA binding properties and domain(s) of TRS1, as well as the functional effects of TRS1 on the PKR and 2-50AS pathways, will be evaluated. The ability of structural homologues of TRS1 in HCMV and murine CMV to bind dsRNA and inhibit these pathways will be evaluated. These results of these studies will provide valuable and novel information regarding viral determinants of CMV pathogenesis.
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| Hakki, Morgan; Marshall, Emily E; De Niro, Katherine L et al. (2006) Binding and nuclear relocalization of protein kinase R by human cytomegalovirus TRS1. J Virol 80:11817-26 |
| Hakki, Morgan; Geballe, Adam P (2005) Double-stranded RNA binding by human cytomegalovirus pTRS1. J Virol 79:7311-8 |
