Valproic acid induces human herpesvirus 8 lytic gene expression in BCBL-1 cells

Valproate is used to treat many neurological diseases that occur in individuals infected with HIV and HHV8. Although valproate stimulates HIV replication in some HIV-infected cell lines in culture, it also enhances zidovudine levels in patients treated with both agents, potentially overcoming any deleterious effect that valproate might have with respect to HIV infection. The results presented here suggest that the use of valproate in patients infected with HHV8 might be detrimental. Plasma concentrations during chronic oral treatment with valproate typically range from 0.28 to 0.69 mM, concentrations that effectively induced lytic gene expression in our studies. The induction of lytic replication by valproate might enhance viral load, potentially triggering the development or exacerbation of Kaposi's sarcoma. Furthermore, several genes that are induced by valproate, using concentrations encountered clinically, could have profound biological effects. For example, vIL-6 is biologically active and has been implicated in the pathogenesis of some forms of Castleman's disease. v-MIP I and vGPCR are angiogenic and vGPCR is oncogenic, suggesting that increased expression of these genes could exacerbate Kaposi's sarcoma. These results should thus be considered when selecting therapy for neurological disease in patients who have HHV8, especially those who have diseases such as Kaposi's sarcoma and Castleman's disease.