Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus

There is substantial evidence that Kaposi sarcoma-associated herpesvirus (K SHV) plays an important role in the pathogenesis of all forms of Kaposi sar coma (KS). It has been noted that KS commonly occurs in locations, such as the feet, where tissue may be poorly oxygenated. On the basis of this obser vation, the potential role of hypoxia in the reactivation of KSHV replicati on was explored by studying 2 KSHV-infected primary effusion lymphoma B-cel l lines (BC-3 and BCBL-1) latently infected with KSHV. Acute and chronic ex posure of these cells to hypoxia (11% O-2) induced KSHV lytic replication, as indicated by an increase in intracellular lytic protein expression and d etection of virus in cell supernatants by Western immunoblotting. In additi on, hypoxia increased the levels of secreted viral interleukin-6. Moreover, hypoxia enhanced the lytic replication initiated by the viral inducer 12-O -tetradecanoylphorbol-13-acetate. Desferoxamine and cobalt chloride, 2 comp ounds that increase the intracellular levels of hypoxia-inducible factor 1, were also able to induce KSHV lytic replication. These studies suggest tha t hypoxia is an inducer of KSHV replication. This process may play an impor tant role in the pathogenesis of KS. (Blood. 2001;97:3244-3250) (C) 2001 by The American Society of Hematology.