Histone Deacetylase Inhibitors Induce Apoptosis with Minimal Viral Reactivation in Cells Infected with Kaposi's Sarcoma-Associated Herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects tumor cells in patients with Kaposi's sarcoma and primary effusion lymphoma (PEL). The purpose of this study was to determine whether histone deacetylase inhibitors (HDAI) could induce apoptosis, with minimal viral replication, in cells latently infected with KSHV. Four HDAI (depsipeptide, suberoylanilide hydroxamic acid, MS-275, and trichostatin A) were studied in two PEL B cell lines (BCBL-1, BC-3). As expected, histone hyperacetylation was readily induced in all PEL cells exposed to HDAI. HDAI also triggered KSHV reactivation in a time- and dose-dependent manner. Flow cytometric and transmission electron microscopic studies, however, revealed that reactivation occurred in only a minor percentage (3–14%) of treated cells. Importantly, and in contrast to viral reactivation, HDAI induced apoptotic cell death in a dose-dependent manner in a large percentage (up to 90%) of KSHV-infected cells. In summary, all four HDAI tested induced histone hyperacetylation in all cells, KSHV reactivation in a minority of cells, and apoptotic cell death in a majority of cells latently infected with KSHV. These findings suggest that HDAI may be a therapeutic option for patients with KSHV-mediated diseases by rendering cells infected with KSHV susceptible to apoptosis.