Cellular determinants of host tropism for herpes simplex virus and pseudorabies virus.

Abstract

Herpes simplex virus (HSV) and Pseudorabies virus (PRV) are related herpesviruses that are important pathogens in their natural hosts. Despite many similarities, differences in interactions of HSV and PRV with their hosts have resulted in the divergence of these viruses into the unique ecological niche enjoyed by each in nature. This thesis research has examined tropism determinants for HSV and PRV and explored how their virus-host interactions influence host range. HSV entry into cells involves initial virus interactions with cell surface heparan sulfate (HS) followed by stable attachment of at least viral glycoprotein D to a non-HS receptor(s). Though porcine cells have functional levels of HS, they are defective in HSV entry. Polyethylene glycol-mediated reversal of the block and transfection of viral DNA show that porcine cells can support HSV replication if entry is bypassed. Also, infant pigs are not susceptible to HSV infection even with intranasal inoculation. We conclude that lack of in vitro and in vivo susceptibility of porcine cells and pigs to HSV can be attributed to absence of functional non-HS receptor(s) important for neutral pH entry. Thus, "non-HS receptor negative" porcine cells and perhaps pigs, provide a novel resource to identify the stable attachment HSV receptor(s) and to study viral entry and pathogenesis. Consistent with absence of reported PRV infection in humans, we find that most cultured human cells of neuronal and non-neuronal tissue origin are restricted in PRV replication. The restriction is at an early post-entry step that influences viral immediate-early gene regulation or function. Intracellular factors that are inhibitors in human cells or are required for replication in native porcine cells influence PRV tropism. Further studies of PRV replication in human cells provide a unique window to examine the influence of host specific cellular factors on regulation of herpesvirus gene expression. The inability of PRV to cause disease in humans, despite its innate ability to efficiently enter into human cells, makes PRV an attractive vector to develop for gene delivery into human cells. Thus, definable or distinct virus-cell interactions in the replicative cycle of HSV and PRV determine the species that they infect.