Effects of NFκB activation on KSHV latency and lytic reactivation are complex and context-dependent

Like all herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) can produce either latent or lytic infection. The latent v-FLIP gene is a strong activator of NF kappa B, and in primary effusion lymphoma (PEL) cells, blockade of NF kappa B activation is associated with enhanced lytic gene expression, while overexpression of p65 impairs expression of reporter genes driven by lytic promoters. This has led to the suggestion that NF kappa B activation may promote latency by suppressing lytic reactivation. Here we examine in detail the effects of NF kappa B activation on KSHV replication in several cell types. In accord with earlier work, we find that inhibition of NF kappa B signaling in PEL cells is associated with enhanced lytic reactivation of KSHV. Similarly, in de novo KSHV infection of primary endothelial cells, inhibition of NF kappa B signaling leads to an increase in lytic gene expression and enhanced virion production. By contrast, KSHV-infected human foreskin fibroblasts (HFF) show no increase in spontaneous lytic reactivation when NF kappa B is inhibited. Moreover, if NF kappa B activation is always inhibitory to lytic gene expression, one might expect its activation to be suppressed during the lytic cycle. However, we find that NF kappa B signaling is strongly and consistently activated in lytically infected cells of all lineages. Together these data indicate that (i) the relationship of NF kappa B activation to latency and lytic reactivation is not uniform, but is dependent on the cellular context; and (ii) even though NF kappa B activation is inhibitory to lytic gene expression in some contexts, such inhibition is at least partially bypassed or overridden during lytic growth. (c) 2007 Elsevier Inc. All rights reserved.