NF-κB Inhibits Gammaherpesvirus Lytic Replication

Abstract

Nasopharyngeal carcinoma, Kaposi's sarcoma, and B-cell lymphomas are human malignancies associated with gammaherpesvirus infections. Members of this virus family are characterized by their ability to establish latent infections in lymphocytes. The latent viral genome expresses very few gene products. The infected cells are therefore poorly recognized by the host immune system, allowing the virus to persist for long periods of time. We sought to identify the cell-specific factors that allow these viruses to redirect their life cycle from productive replication to latency. We find that the cellular transcription factor NF-B can regulate this process. Epithelial cells and fibroblasts support active (lytic) gammaherpesvirus replication and have low NF-B activity. However, overexpression of NF-B in these cells inhibits the replication of the gammaherpesvirus murine herpesvirus 68 (MHV68). In addition, overexpression of NF-B inhibits the activation of lytic promoters from MHV68 and human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). In lymphocytes latently infected with KSHV or EBV, the level of NF-B activity is high, and treatment of these cells with an NF-B inhibitor leads to lytic protein synthesis consistent with virus reactivation. These results suggest that high levels of NF-B can inhibit gammaherpesvirus lytic replication and may therefore contribute to the establishment and maintenance of viral latency in lymphocytes. They also suggest that NF-B may be a novel target for the disruption of virus latency and therefore the treatment of gammaherpesvirus-related malignancies.

A requirement for NF-κB induction in the production of replication-competent HHV-8 virions

“…Our results are apparently at odds with a recent study of Brown et al (2003), who in their reporter gene model demonstrated that overexpression of p65 represses the transactivation potential of ORF 50, a protein involved in the switch to lytic replication. They argue that high levels of NF-kB may activate a cellular protein that participates in the repression of gammaherpesvirusspecific gene expression, therefore inhibiting lytic replication.…”

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

“…Lastly, gammaherpesviruses establish latent infections in lymphocytes and are implicated in nasopharyngeal carcinoma, Kaposi's sarcoma and B-cell lymphomas. NF-kB was recently implicated in promoting latency in gammaherpesvirusinfected cells, as its overexpression in epithelial and fibroblast cells suppressed replication of murine herpesvirus 68 (MHV68) and blocked activation of lytic promoters from MHV68 and Kaposi's sarcoma-associated herpesvirus (KSHV) (Brown et al, 2003). In contrast, NF-kB inhibition in KSHV-infected cells led to lytic protein synthesis and virus reactivation.…”

In vitro EBV-infected subline of KMH2, derived from Hodgkin lymphoma, expresses only EBNA-1, while CD40 ligand and IL-4 induce LMP-1 but not EBNA-2

“…43 Signals from CD40 and LMP-1 and activated NF-B are known to inhibit the entry into lytic cycle. 44,45 Since NF-B is constitutively activated in H/RS cells and in the HL-derived cell lines as well, 46 this may explain why lytic replication was not induced in the KMH2 EBV cells.…”