The elimination of neurotropic viruses such as herpes simplex virus (HSV) from the nervous system is likely to be complex, and to involve other mechanisms besides direct lysis of infected cells by cytotoxic T cells (CTL) because MHC antigens are not normally expressed in the nervous system. Preliminary studies have revealed an extensive and prolonged inflammatory response in the mouse trigeminal ganglion (TG) and brain stem during latency. T cells associated with secreted IFN-g were focused around neurons that appeared morphologically normal, some of which were latently infected with HSV. TNF-a and IL-2 transcripts were also detected during latency. Based on the investigators preliminary studies and published studies of others, it is hypothesized that IFN-g and TNF play an important role in suppressing HSV replication at the acute stage contributing to the survival of infected neurons, and it is speculated further that they might also function to modulate the frequency of detectable reactivation. In this application an immune-PCR assay will be used to determine whether HSV antigens are expressed in the ganglion and brain during latency and the cytokine profile in these tissues will be determined by RNAse protection assay. The investigators will determine the extent to which IFN-g and TNF-a synergize to control HSV replication in the nervous system by comparing the course of infection in control, IFN-g knockout (gko) and TNF receptor knockout (TNFR1,2) mice inoculated with wild type HSV, or a HSV recombinant (HSV-g) that expresses an IFN-g transgene. An HSV mutant (HSV-gR) engineered to express the IFN-g receptor (IFN-gR) will be used in studies with IFN-g receptor knockout (Rgko) mice to determine whether the effects of IFN-g are mediated through interaction with the receptor on infected neurons and other cells. The potential of IFN-g and TNF to modulate the frequency of detectable HSV reactivation once initiated will be examined in latently infected Rgko mice, gko mice, and control mice inoculated with type HSV-gR, and subjected to transient hypothermia as a reactivation stimulus. Studies proposed here aim to enhance our understanding of the role of IFN-g and TNFa/b in the control of acute HSV infections in the nervous system and clarify their role in latency. Since episodes of chronic IFN-g secretion have been demonstrated during HSV infection in the nervous system, HSV may be involved in a variety of neurological disorders associated with increased cytokine expression in the brain.
