de novo synthesis of vp16 coordinates the exit from hsv latency in vivo从头合成的vp16坐标退出hsv延迟体内.pdf

De Novo Synthesis of VP16 Coordinates the Exit from HSV Latency In Vivo 1 2 3 Richard L. Thompson , Chris M. Preston , Nancy M. Sawtell * 1 Department of Molecular Genetics, Microbiology, and Biochemistry, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America, 2 Medical Research Council Virology Unit, Glasgow, Scotland, United Kingdom, 3 Department of Pediatrics, Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America Abstract The mechanism controlling the exit from herpes simplex virus latency (HSV) is of central importance to recurrent disease and transmission of infection, yet interactions between host and viral functions that govern this process remain unclear. The cascade of HSV gene transcription is initiated by the multifunctional virion protein VP16, which is expressed late in the viral replication cycle. Currently, it is widely accepted that VP16 transactivating function is not involved in the exit from latency. Utilizing the mouse ocular model of HSV pathogenesis together with genetically engineered viral mutants and assays to quantify latency and the exit from latency at the single neuron level, we show that in vivo (i) the VP16 promoter confers distinct regulation critical for viral replication in the trigeminal ganglion (TG) during the acute phase of infection and (ii) the transactivation function of VP16 (VP16TF) is uniquely required for the exit from latency. TG neurons latently infected with the VP16TF mutant in1814 do not express detectable viral proteins following stress, whereas viruses with mutations in the other major viral transcription regulators ICP0 and ICP4 do exit the latent state. Analysis of a VP16 promoter/reporter mutant in the background of in1