title: Activation of human herpesvirus replication by apoptosis.
abstract: A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents, like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g., butyrate) was thought to end latency. We recently showed that Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the replication and transcription activator (RTA) protein, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology, we studied cell lines latently infected with Epstein-Barr virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, which suggests that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance.
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Prasad
authors.forename: Jill
authors.initials: J
authors.lastname: Remick
authors.forename: Steven L
authors.initials: SL
authors.lastname: Zeichner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000235:genetics; D006564:Herpesviridae / Q000145:classification / Q000502:physiology*; D006566:Herpesviridae Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D006801:Humans; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D000970:Antineoplastic Agents; D004279:DNA, Viral; D012333:RNA, Messenger; D014764:Viral Proteins; D053148:Caspase 3