920 the Non-Coding Control Region of Trichodysplasia Spinulosa Polyomavirus is Responsible for Cell-Type Specific Viral Gene Expression in Vivo

Trichodysplasia spinulosa is a rare hair follicle disorder that develops in immunosuppressed patients and is associated with productive infection by a polyomavirus designated TSPyV. Affected hair follicles contain a crescent-like hair matrix, a massively expanded compartment of aberrantly proliferating inner root sheath (IRS)-like cells, and disorganized hair shaft-like cells. The TSPyV genome contains an early region encoding transforming antigens (TAgs) responsible for viral genome replication, and the late region encoding structural proteins needed for assembly of virions during productive infection. Both early and late gene expression is controlled by a bidirectional regulatory domain called the non-coding control region (NCCR). In trichodysplasia spinulosa, early genes are expressed in hair matrix and IRS-like cells, but the molecular basis for this precise cell-type specificity is not known. We tested the hypothesis that the NCCR plays a pivotal role in defining where and when viral genes are expressed in vivo by mapping the expression pattern of a TSPyV NCCR-driven fluorescent reporter and viral early region genes in transgenic mice. We found that the TSPyV NCCR drives reporter and viral gene expression (large TAg) in matrix and IRS-like cells in both preterm embryos and adult transgenic mice. Additionally, a large fraction of IRS cells co-expresssed the differentiation marker TCHH and proliferation marker Ki67, reflecting the aberrant proliferation of this normally post-mitotic cell type in human trichodysplasia spinulosa. These data uncover a critical role for the TSPyV NCCR in restricting expression of viral genes to specific cell type in vivo, and establish that early viral gene expression is sufficient to drive proliferation in normally quiescent IRS-like cells.