FIG 8.

Working model summarizing bidirectional regulation from the BK polyomavirus NCCR. The transcription factors Sp1, Ets1, and NF-1 determine the strength and direction of gene expression toward EVGR (early; red arrow) and LVGR (late; green arrow). (Top) The archetype ww(1.4) NCCR mediates basal activity with low EVGR expression (dashed arrow) and high LVGR expression (green arrow). Sp1 and Ets1 contribute a directional effect on neighboring Sp1 and Ets1, whereas NF1 has a stabilizing effect. (Center) Mutant NCCR phenotypes, according to EVGR and LVGR expression. The group 1 TFBS mediate a major contribution of Sp1 or Ets1 to LVGR expression, which is abrogated in their absence and results in a net increase of EVGR expression. Group 2 TFBS stabilize Sp1 and Ets1 locally and thereby contribute to LVGR and EVGR expression in a partly position-dependent way. Group 3 TFBS are essential for EVGR and LVGR expression, since in their absence, mutants show low viral expression. This suggests that binding to SP1-2 is of overall importance for EVGR and LVGR expression, with possible implications for latency. (Bottom) Patient isolates with rr del(5.3) and ins(7.3) NCCRs result in part from group 1 and 2 mutant effects. In addition, NF1 sites in the center of the NCCR may interfere in an insulator-like fashion with the presumed Sp1 action from SP1-2 on LVGR expression.