Nevertheless, the ability of Hsp90 inhibitors PS-341 Velcade to decrease expression and/ or function of certain cellular proteins, particularly NF κB, no doubt collaborates with the loss of EBNA1 to induce killing of EBV transformed LCLs. Interestingly, as PS-341 Velcade we also found that expression of the EBV protein LMP1 is rather dramatically increased by Hsp90 inhibitors, and high level LMP1 expression is toxic, LMP1 overexpression may also contribute to the death of LCLs. The antiapoptotic effect ofEBNA1 may normally attenuate the toxicity of LMP1. Finally, we also demonstrated that a nontoxic dose of 17 AAG effectively inhibits the growth of EBV induced lymphoproliferative disease in SCID mice.
In addition to EBNA1, recent evidence suggests that some other important viral proteins also require Hsp90 for proper folding and/ or stability.
For example, poliovirus Clinofibrate capsid protein P1 is expressed at only low levels in the presence of Hsp90 inhibitors, and geldanamycin treatment prevents the death of poliovirus infected mice. Geldanamycin and 17 AAG delay growth of influenza A virus in cell culture and reduce half life of the PB1 and PB2 subunits of the viral RNA polymerase Clinofibrate complex. Hsp90 is also required for lytic replication of HSV 1 and human cytomegalovirus. Our results suggest that Hsp90 inhibitors might be useful for treating a variety of different EBV induced diseases, provided that the continued presence of the viral genome is required for these EBV associated illnesses.

Given our finding that Hsp90 inhibitors prevent EBV transformation of B cells in vitro and inhibit the growth of EBV induced lymphoproliferative disease in SCID mice, the most obvious target for Hsp90 inhibitor therapy in humans would be EBV induced lymphoproliferative disease. In this disease, each of the known EBV encoded transforming proteins is expressed, and there is little doubt that the continued presence of EBV is required for growth of these lesions. Another often fatal illness that appears to be highly dependent upon the presence of EBV, and might thus respond to Hsp90 inhibitors, is chronic active EBV disease.
This rare disease, which most commonly occurs in Asia, is caused by persistent latent EBV infection of T cells and/or natural killer cells, and frequently culminates in EBV positive T cell/natural killer cell malignancies.
Whether the loss of EBNA1 expression induced by Hsp90 inhibitors in EBV positive tumors such as Hodgkin lymphoma, NPC, gastric carcinoma, and Burkitt lymphoma, which have additional genetic abnormalities and express only a subset of the EBV transforming proteins, would result in EBV dependent killing is less clear. However, given that inhibition of EBNA1 induces apoptosis in most EBV positive Burkitt lymphoma cells in vitro and reduces the growth and survival of some EBV positive epithelial tumors, these malignancies may indeed continue to require EBNA1 expression for their growth in vivo, similar to the recently described oncogene addiction theory for cellular oncogenes. Finally, it is interesting to speculate whether Hsp90 inhibitors could be used to treat nonmalignant illnesses associated with EBV infection. In the case of EBV induced IM, Hsp90 inhibitors would be predicted to not only reduce the number of cells infected with EBV, but would also likely atte