The herpesviruses are well adapted to their hosts, and employ a variety of mechanisms to co-exist with the host immune response. Recently, we have described the ability of herpes simplex virus (HSV)-infected cells to send a negative signal that durably inhibits normal CTL function, a phenomenon we have called """"""""inactivation"""""""". Mutant HSV strains lacking the Us3 kinase do not induce inactivation. Inactivation requires direct contact between HSV-infected cells and CTL, and appears to result via a virally encoded ligand. Inactivated CTL do not perform granule-mediated cytotoxicity or secrete the cytotoxic cytokines TNF and IFN-gamma in response to stimulation via the T cell receptor, yet retain the ability to synthesize cytokines after stimulation by PMA/ionomycin. Inactivated CTL show no signs of apoptosis, and remain inactivated for at least 12-48 hours. Taken together, these data suggest that HSV is exploiting an unidentified and extremely powerful signaling pathway that can lead to a profound and durable inhibition of CTL activity. To investigate the molecular events involved in the inactivation process, we propose the following.
Specific Aim 1. Determine whether expression of the HSV protein Us3 alone is sufficient for the inactivation effect, or requires interaction with other viral proteins. We will express Us3 in isolation from other viral genes in fibroblasts, and determine whether Us3-expressing cells can inactivate CTL.
Specific Aim 2. Identify the ligand transmitting the inactivating signal to CTL, and the role of Us3 in its expression. Our preliminary data suggest that the inactivating ligand is of viral rather than cellular origin. We will identify the ligand sending the inactivating signal by expressing individual HSV candidate proteins, and using mutant HSV strains with deletions of individual genes.
Specific Aim 3. Determine the intracellular signaling events associated with inactivation of CTL, and the effects of inactivation on signaling via the T cell receptor. We will investigate the role of a 90-kDa protein phosphorylated in inactivated but not control CTL. We will also evaluate the effect of inactivation on intracellular signaling events resulting from T cell receptor ligation. Elucidation of the molecular details of the inactivation pathway will provide fundamental insight into the regulation of CTL. The understanding of this pathway may also suggest rational targets for pharmacological manipulation of CTL function.
| Han, Jin-Young; Miller, Sara A; Wolfe, Teresa M et al. (2009) Cell type-specific induction and inhibition of apoptosis by Herpes Simplex virus type 2 ICP10. J Virol 83:2765-9 |
| Han, Jin-Young; Sloan, Derek D; Aubert, Martine et al. (2007) Apoptosis and antigen receptor function in T and B cells following exposure to herpes simplex virus. Virology 359:253-63 |
