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Varicella-zoster virus (VZV) causes varicella (chickenpox) and zoster (shingles). Our laboratory investigates the molecular virology of VZV, focusing on the functional roles of particular viral gene products in pathogenesis and virus-cell interactions in differentiated human cells in SCID mouse models of VZV infection in vivo. Aspects of VZV tropism are investigated using SCID mice that have human skin, T cell and dorsal root ganglion xenografts and VZV recombinant viruses that have targeted mutations of viral promoters, open reading frames and non-coding regions. The consequences of targeted mutations in the VZV genome reveal functions that are important for VZV pathogenesis and that counteract intrinsic cellular regulation of VZV replication. These studies provide information relevant for developing new genetically engineered vaccines to reduce the disease burden of VZV infections.