Identification of the In Vivo Role of a Viral bcl-2

Abstract

Many γ-herpesviruses encode candidate oncogenes including homologues of host bcl-2 and cyclin proteins (v-bcl-2, v-cyclin), but the physiologic roles of these genes during infection are not known. We show for the first time in any virus system the physiologic role of v-bcl-2. A γ-herpesvirus v-bcl-2 was essential for efficient ex vivo reactivation from latent infection, and for both persistent replication and virulence during chronic infection of immunocompromised (interferon [IFN]-γ−/−) mice. The v-cyclin was also critical for the same stages in pathogenesis. Strikingly, while the v-bcl-2 and v-cyclin were important for chronic infection, these genes were not essential for viral replication in cell culture, viral replication during acute infection in vivo, establishment of latent infection, or virulence during acute infection. We conclude that v-bcl-2 and v-cyclin have important roles during latent and persistent γ-herpesvirus infection and that herpesviruses encode genes with specific roles during chronic infection and disease, but not acute infection and disease. As γ-herpesviruses primarily cause human disease during chronic infection, these chronic disease genes may be important targets for therapeutic intervention.

BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2

“…42 Yet other work suggests that BCL-2 homologs are more important for reactivation or persistent infection. 43 Their role in cancer is equally undecided, and understanding has been limited by the poor availability of good antibodies recognizing the proteins. However, transcripts of KSHV BCL-2 have been detected in cell lines and clinical samples from primary effusion lymphoma and KS.…”

Involvement of Noxa in Cellular Apoptotic Responses to Interferon, Double-stranded RNA, and Virus Infection

“…Viruses also target the Bcl-2 family (56), and roles for apoptosis in both the propagation and suppression of virus replication have been described (1). With few exceptions (40), however, the in vivo functions of these proteins are largely unknown. Lytic viruses may utilize host apoptotic cascades to aid in cell destruction and virus dissemination, and cells counter with sensitive detection systems to attempt to short circuit replication by undergoing an "altruistic" apoptosis before the virus has completed the entire replication process (53).…”

Solution structure of a Bcl-2 homolog from Kaposi sarcoma virus

“…Dysregulation of these processes helps the virus to survive and successfully replicate. Recent in vivo work has shown that the gammaherpesvirus expresses several cellular protein mimics including a viral-cyclin and a viral-bcl-2 that are critical for viral reactivation from latency and replication in immunocompromised hosts (5). Furthermore, these viral genes likely increase the propensity for oncogenic transformation of virus-infected cells based on their ability to interfere with established tumorsuppressor pathways (2).…”