title: Reactivation of Kaposi's sarcoma-associated herpesvirus by natural products from Kaposi's sarcoma endemic regions.
abstract: Kaposi's sarcoma (KS) and its causative agent, Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8), a gamma2 herpesvirus, have distinctive geographical distributions that are largely unexplained. We propose the "oncoweed" hypothesis to explain these differences, namely that environmental cofactors present in KS endemic regions cause frequent reactivation of KSHV in infected subjects, leading to increased viral shedding and transmission leading to increased prevalence of KSHV infection as well as high viral load levels and antibody titers. Reactivation also plays a role in the pathogenesis of KSHV-associated malignancies. To test this hypothesis, we employed an in vitro KSHV reactivation assay that measured increases in KSHV viral load in KSHV infected primary effusion lymphoma (PEL) cells and screened aqueous natural product extracts from KS endemic regions. Of 4,842 extracts from 38 countries, 184 (5%) caused KSHV reactivation. Extracts that caused reactivation came from a wide variety of plant families, and extracts from Africa, where KSHV is highly prevalent, caused the greatest level of reactivation. Time course experiments were performed using 28 extracts that caused the highest levels of reactivation. The specificity of the effects on viral replication was examined using transcriptional profiling of all viral mRNAs. The array data indicated that the natural extracts caused an ordered cascade of lytic replication similar to that seen after induction with synthetic activators. These in vitro data provide support for the "oncoweed" hypothesis by demonstrating basic biological plausibility.
authors.affiliation: Viral Epidemiology Section, AIDS Vaccine Program, SAIC-Frederick, NCI-Frederick, Frederick, MD 21702, USA. whitbyd@ncifcrf.gov
authors.forename: Denise
authors.initials: D
authors.lastname: Whitby
authors.forename: Vickie A
authors.initials: VA
authors.lastname: Marshall
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Bagni
authors.forename: Wendell J
authors.initials: WJ
authors.lastname: Miley
authors.forename: Thomas G
authors.initials: TG
authors.lastname: McCloud
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hines-Boykin
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.forename: Betty A
authors.initials: BA
authors.lastname: Conde
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.forename: Judy
authors.initials: J
authors.lastname: Mikovits
authors.forename: Dirk P
authors.initials: DP
authors.lastname: Dittmer
authors.forename: David J
authors.initials: DJ
authors.lastname: Newman
mesh_terms: D001681:Biological Assay; D001688:Biological Products / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004777:Environment; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005843:Geography; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D012514:Sarcoma, Kaposi / Q000648:ultrastructure / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D001688:Biological Products; D010936:Plant Extracts; D012333:RNA, Messenger