The herpes simplex viruses (HSV) establish lifelong infection in their host. These viruses are thought to have evolved in parallel with their hosts, and therefore have developed intricate strategies for co-existing with the immune response. In preliminary studies for this proposal, I have demonstrated that HSV-1 inhibits the oligonucleosomal DNA fragmentation characteristic of apoptosis, including apoptosis induced by CTL. Since recent reports suggest that cells undergoing apoptosis are not suitable for viral replication, the induction of apoptosis may be a critical function for CTL control of viral infection. Inhibition of apoptosis would therefore promote viral replication. In contrast to its inhibition of DNA fragmentation, HSV has no effect on the membrane manifestations of apoptosis, such as phosphatidylserine exposure. In this proposal, the ability of HSV-2 to inhibit apoptosis will be evaluated. The HSV-1 and -2 genes mediating the anti-apoptotic effect will be identified, using compounds limiting HSV gene expression to individual transcriptional classes, followed by analysis of HSV deletion mutants. The cellular targets of each HSV anti-apoptotic gene will be identified using the yeast two-hybrid system. Finally, the ability of HSV to interfere with different apoptosis-inducing mechanisms of CTL will be determined using anti-Fas antibody and isolated perforin and cytotoxic granule components. The results of these studies will improve our understanding of HSV evasion of the immune response, and may suggest therapeutic strategies to circumvent this evasion. In addition, these studies will provide new probes and insight into the cascade of intracellular events following induction of apoptosis, especially the terminal effector events, since HSV inhibits nuclear but not membrane events of apoptosis. The work will also provide insights into how the manifestations of apoptosis vary depending on the inducing stimulus.
| Jerome, K R; Chen, Z; Lang, R et al. (2001) HSV and glycoprotein J inhibit caspase activation and apoptosis induced by granzyme B or Fas. J Immunol 167:3928-35 |
| Jerome, K R; Fox, R; Chen, Z et al. (2001) Inhibition of apoptosis by primary isolates of herpes simplex virus. Arch Virol 146:2219-25 |
| Jerome, K R; Fox, R; Chen, Z et al. (1999) Herpes simplex virus inhibits apoptosis through the action of two genes, Us5 and Us3. J Virol 73:8950-7 |
