Nelfinavir Activates Epstein-Barr Virus and Kaposi's Sarcoma Herpesvirus Lytic Cycle by Inducing ER Stress

Epstein-Barr virus (EBV) and Kaposi's Sarcoma herpesvirus (KSHV) are associated with lymphomas and other malignancies. We previously demonstrated that the proteasome inhibitor, bortezomib, leads to ER stress, induction of the unfolded protein response (UPR), and activation of EBV lytic gene expression.¹  Here we investigate nelfinavir, an HIV protease inhibitor that has been reported to induce the UPR.²  Nelfinavir treatment of EBV Burkitt's lymphoma (BL) and KSHV primary effusion lymphoma (PEL) cell lines resulted in changes indicative of ER stress: elevated levels of ATF4, XBP1(s), and CHOP10 (Figure 1), as well as the EBV and KSHV immediate early proteins ZTA and RTA (Figure 2), respectively. The appearance of these UPR markers preceded expression of viral lytic RNAs. Regulated knockdown of Bip, an ER-stress sensor and activator of the UPR, by shRNA inhibited viral lytic RNA induction. These effects were observed using drug levels at or just above the levels achieved with standard clinical dosing of nelfinavir. Gantt et al. have reported that nelfinavir inhibits herpes virion production, including KSHV, in vitro.³  The ability to activate viral gene expression in combination with inhibition of virion production may identify nelfinavir as an especially promising agent for virus-targeted cancer therapies.