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The primary focus of our lab is on the neuronal mechanisms
that regulate the establishment and maintenance of latent neuronal
infection with herpes simplex virus (HSV). To acccomplish this we
are using three basic strategies. The first has been to use transgenic
mice that carry viral IE promoter constructs to characterize differential
endogenous expression of key HSV regulatory genes in two distinct
neuronal populations (IB4+ and A5+) with markedly different outcomes
of infection (lytic vs latent). The second strategy has to probe murine
cDNA expression arrays in order to identify host genes that are differentially
expressed in the A5+ and IB4+ neuronal populations. Differentially
expressed neuronal genes are then assayed for their ability to activate
or inhibit key regulatory viral genes,. The third strategy has been
to screen a neuronal cDNA library for gene products that down regulate
HSV IE promoter activity. Using this screen we have identified a novel
gene (IF-1) that represses HSV ICP4 promoter activity as well as HSV
productive infection by up to 99%. IF-1 has homology to the KRAB A
domain of a large family of transcriptional regulatory genes and by
in situ hybridization is selectively expressed in primary sensory
neurons of the trigeminal ganglion. We are currently engineering an
HSV construct that will overexpress the IF-1 gene in order to test
whether expression of this gene in TG neurons in vivo inhibits productive
viral infection, thus driving neuronal infection with HSV toward latency. |
Biomedical Sciences (BMS) Graduate Program
