Abstract:
Herpes simplex virus type 1 (HSV-1) is a neurotropic virus affecting up to 98% of the adult population. Central to this report is the proteinaceous layer termed the tegument found within the HSV-1 virion. The tegument is composed of >20 different viral proteins of varying stoichiometries. Tegument proteins are delivered to the host cell upon infection, providing this virus an advantage early in its replication cycle. Tegument proteins also function at late times in infection when they are synthesized at high levels. One of the most abundant tegument proteins is VP22, encoded by the U_L 49 gene, with over 2000 copies per virion. The studies described herein provided much insight into how VP22 promotes the HSV-1 replication cycle. We found the absence of VP22 during infection resulted in decreased mRNA levels at early times and decreased protein synthesis at late times. These results were distinct and separable with respect to both the genes affected and the timing during infection. Because U_L 49^- infections often result in secondary, compensatory mutations in the gene encoding vhs, we examined the effects of one such mutation as well as the role of vhs's RNase activity on protein synthesis in the presence and absence of VP22. Our results indicated secondary mutations that decreased vhs's RNase activity compensated for the lack of VP22 during HSV-1 infections. Further analyses indicated the absence of VP22 resulted in decreased translation efficiency independent of mRNA abundance, the result of cleavage of the 5' UTRs of viral mRNAs. In separate studies we focused on the tegument protein encoded by the U_L21 gene. Although much is known about the role of this protein at late times in infection, very little was known about its role at early times in HSV-1 infections. We found the absence of pUL21 resulted in decreased levels of several immediate early mRNAs, and their corresponding proteins, at early times in infection. Although HSV-1 establishes a persistent infection, and is therefore incurable, we have made several novel findings that contribute important knowledge to the herpesvirus field and will hopefully aid in the development of new therapeutics.
