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

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Abstract
The gammaherpesvirus human herpesvirus 8 (HHV-8) infects endothelial and B-lymphoid cells and is responsible for the development of Kaposi's sarcoma and primary effusion lymphoma (PEL). In the present study, we demonstrate that the activation of the NF-B pathway during HHV-8 lytic replication is required for the generation of replication-competent virions capable of initiating a de novo infection of endothelial cells. In the HHV-8-positive PEL cell line BCBL-1, tetradecanoyl phorbol acetate (TPA) induction of the lytic cycle activates the NF-B pathway, and this activation requires the induction of the IKK component of the classical IB kinase (IKK) complex. To further investigate the role of NF-B activation in HHV-8 lytic replication, the NF-B super-repressor IB-2N4 was introduced into BCBL-1 cells by retroviral transduction. Expression of IB-2N4 completely abolished NF-B activity, as demonstrated by the loss of NF-B DNA-binding activity and the absence of expression of the endogenous, NF-B-regulated IB gene. NF-B blockade dramatically impaired the ability of HHV-8 to produce infectious particles capable of initiating an effective de novo infection of endothelial EA.hy926 cells, as demonstrated by the lack of viral protein production in the target cells. Diminished infectivity did not appear to be caused by a reduction in virus titer, as demonstrated by equivalent viral DNA content in the supernatant of TPA-stimulated BCBL-1 and BCBL-1/2N4 cells. Although the viral and/or cellular products affected by NF-B inactivation remain to be fully characterized, these data demonstrate an unexpected role for NF-B induction during lytic reactivation in the production of replication-competent HHV-8 virions.

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