Effects of NFkappaB 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 NFkappaB, and in primary effusion lymphoma (PEL) cells, blockade of NFkappaB 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 NFkappaB activation may promote latency by suppressing lytic reactivation. Here we examine in detail the effects of NFkappaB activation on KSHV replication in several cell types. In accord with earlier work, we find that inhibition of NFkappaB signaling in PEL cells is associated with enhanced lytic reactivation of KSHV. Similarly, in de novo KSHV infection of primary endothelial cells, inhibition of NFkappaB 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 NFkappaB is inhibited. Moreover, if NFkappaB activation is always inhibitory to lytic gene expression, one might expect its activation to be suppressed during the lytic cycle. However, we find that NFkappaB signaling is strongly and consistently activated in lytically infected cells of all lineages. Together these data indicate that (i) the relationship of NFkappaB activation to latency and lytic reactivation is not uniform, but is dependent on the cellular context; and (ii) even though NFkappaB activation is inhibitory to lytic gene expression in some contexts, such inhibition is at least partially bypassed or overridden during lytic growth.
Grossmann
Claudia
C
Howard Hughes Medical Institute, San Francisco 94143, USA; Department of Medicine, University of California, San Francisco 94143, USA; Department of Microbiology, University of California, San Francisco 94143, USA.
Ganem
Don
D
D002478:Cells, Cultured; D042783:Endothelial Cells / Q000821:virology; D005347:Fibroblasts / Q000821:virology; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D016328:NF-kappa B