The role of cyclin D3 in the replication of herpes simplex virus 1.

摘要

The infected cell protein No. 0 (ICP0) of herpes simplex virus 1 (HSV-1) acts as a promiscuous transactivator and is particularly important for viral replication in cells infected at low multiplicity but appears to be nonessential for viral replication. The mechanism by which ICP0 accomplishes this task is unknown but clues based on interactions found with host proteins, such as the infected host cyclin D3, may aid in our understanding of the contribution ICP0 plays in viral replication.; This research found that HSV-1 ICP0 binds and stabilizes cyclin D3 but does not affect the cyclins known functions. Substitution of aspartic acid 199 with alanine precluded the interaction of this protein with cyclin D3 in the yeast two-hybrid system. A D199A point mutant was constructed and the destabilization of cyclin D3 in mutant-infected cells was equivalent to that of cells infected with the ICP0 null recombinant. The mutant virus yielded 10 fold less progeny from infected resting cells. In mice, the mutant was only slightly less pathogenic than the wild-type parent by intracerebral route but was significantly less neuroinvasive following a peripheral inoculation. Additionally results indicate that interaction of ICP0 with cyclin D3 correlates with two events: the stabilization and activation of G1-phase cyclins via cyclin dependant kinases and the translocation of ICP0 from the nucleus to the cytoplasm. These observations provide evidence that the association of ICP0 with cyclin D3 is employed by the virus to scavenge host cell cycle machinery so as to enhance viral replication.