Project: Research project

Project Details


Herpes simplex virus type 1 (HSV-1) is a common oral and genital
pathogen that is also a leading cause of kerato-conjunctivitis leading to
blindness and encephalitis. More serious and disseminated disease occurs in
immune deficient individuals including neonates and AIDS patients. Encephalitic
(neuroinvasive disease in the mouse model) and neonatal disease production are
complex processes. It is not known which host selective pressures (e.g. the
immune response, the target tissue (neuronal and other cells)) are important
for selecting neuroinvasive disease determinants. As a result, naturally
selected disease producing HSV-laboratory strains hold the clues to
understanding the virulence mechanisms of HSV-1. Upon comparison of clinical
isolates and attenuated laboratory strains, a strong correlation between
neuroinvasive disease potential and the small plaque phenotype (tissue culture
behavior characterized by small plaque production, a block in glycoprotien
processing and inefficient virus release) was noted. The small plaque phenotype
was mapped to near the ICP34.5 gene and genetic differences in ICP34.5
correlate with virulence and attenuation of neuroinvasive disease. The
prototype virus (SP7) is a neuroinvasive, small plaque clinical isolate
obtained from the brain of a neonate. Passage of SP7 yielded viruses (SLP5,
SLP10) that are attenuated, produce large plaques and have and ICP34.5 gene
that resembles the highly passaged, attenuated KOS virus strain. These and
other studies indicate the importance of the ICP34.5 gene and protein for
neuroinvasive disease and suggest that difference in the ICP34.5 gene and
protein change the nature of the virus-cell and virus-host interactions. The
purpose of this study is to further our understanding of the structure and
function of ICP34.5 and its role in the neuroinvasive disease process and as a
result gain a better understanding of HSV interactions with cells and the host.
The unique aspect of these studies will be in comparison of variants in ICP34.5
generated by natural selection of HSV-1 in the human host, by tissue culture
passage or by insertion of ICP34.5 gene sequences from SP7 into SLP5 or SLP10.
They will compare the behavior of the ICP34.5 variants in neuronal and other
cells and a mouse model of encephalitis and also the protein expressed from
eukaryotic expression vectors containing PCR amplified ICP34.5 gene sequences
from the same variants.
StatusNot started