SIGNAL INDUCTION AFTER HERPES SIMPLEX VIRUS INFECTION

University Of North Carolina Chapel Hill, Chapel Hill NC

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Linked publications & trials

Abstract

Herpes simplex virus can establish productive infections in cycling epithelial cells, and post-mitotic, differentiated neurons. HSV can also establish a latent infection in sensory neurons of dorsal root ganglia. Initial steps in the infection process require stable attachment and envelope fusion, both mediated by viral glycoproteins. This research proposal is based on our observations that NF-kappaB and cJUN, targets of the MAPK and SAPK signal transduction cascades, respectively, are activated following HSV infection. NF-kappaB is transiently activated as a result of virus attachment, and later around the time of DNA synthesis. In contrast, cJUN is not activated at the time of virus attachment, but rather with delayed-early kinetics. The specific aims of the proposal are designed to address mechanistic aspects of signal transduction pathway activation, and to determine the importance of targeting NF-kappaB and cJUN for the replication of HSV. In this way we hope to further our understanding of how protein kinase signal transduction pathways contribute to the pathobiology of lytic herpes simplex virus infection. Information gathered under the proposed research project should, in addition, inform us of potential mechanisms which allow establishment and maintenance of HSV latency. The over-all experimental approach will be to identify effects of virus infection on the SAPK signal transduction pathway, and selected activating pathways for NF-kappaB, then to deliberately promote or inhibit that pathway, and finally to measure the consequences through various readouts of virus replication. This will enable us to differentiate between non-specific and critical outcomes of virus infection on cell functions. Through the use of 1) adenovirus vector based over-expression of signal transduction proteins, 2) cells either deleted for specific genes, or expressing activated or dominant-negative alleles of signal transduction pathway proteins, and 3) drugs which target specific steps in signal transduction pathways, conditions will be created against which aspects of the HSV replication cycle can be evaluated.