HCMV complementation of replication-deficient adenovirus inhibits HCMV replication
Berkowitz, Jonathan Laurence
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Most DNA viruses, including adenovirus and human cytomegalovirus (HCMV), assume control of the cell cycle to provide an optimal environment for viral replication. These viruses do this, in part, by activating E2F-regulated gene expression. Since this activation causes the induction of p53, which inhibits E2F by inducing p21, it is essential that the viruses disable p53. These effects on E2F and p53 create an environment similar to that seen in cancer cells, an environment more conducive to viral replication than seen in normal cells. Not surprisingly, adenoviruses that are replication-deficient in normal cells (RAd) because they lack the genes that target E2F and p53, can selectively replicate in and lyse cancer cells through the shutdown of host cell protein synthesis. Thus, they have shown promise as anti-cancer agents. Recently, one study demonstrated that RAd prevented replication of human immunodeficiency virus (HIV). Since HIV activates E2F and disables p53 to create an environment similar to that within cancer cells, the RAd may replicate in the presence of HIV and shutdown host cell protein synthesis before the completion of HIV replication. HCMV has been demonstrated to have effects on E2F and p53 similar to those of HIV. Therefore, the consequences of the co-infection with HCMV and RAd on E2F-dependent gene expression, host cell protein synthesis and viral replication have been examined. Our results demonstrate that HCMV alone induced E2F-dependent gene expression without inducing p21. Correspondingly, HCMV rescued RAd replication, which led to a shutdown of host cell protein synthesis. Since this shutdown correlated with decreased expression of both E2F-dependent and HCMV genes, it followed that RAds blocked HCMV replication. Lastly, the inhibition of HCMV replication correlated with the presence of RAd replication. These findings are consistent with the hypothesis that the shutdown of host protein synthesis is the mechanism by which RAds inhibit HCMV replication. Thus, a selective inhibition of host protein synthesis in virally-infected cells presents a novel approach to anti-viral therapies. This approach may offer the possibility of decreased viral resistance to therapy, because of the extensive effects on the host.