Abstract
Epstein-Barr virus (EBV) is a human herpesvirus that causes infectious mononucleosis and contributes to both B-cell and epithelial-cell malignancies. EBV-infected epithelial cell tumors, including nasopharyngeal carcinoma (NPC), are largely composed of latently infected cells, but the mechanism(s) maintaining viral latency are poorly understood. Expression of the EBV BZLF1 (Z) and BRLF1 (R) encoded immediate-early (IE) proteins induces lytic infection, and these IE proteins activate each other’s promoters. ΔNp63α (a p53 family member) is required for proliferation and survival of basal epithelial cells and is over-expressed in NPC tumors. Here we show that ΔNp63α promotes EBV latency by inhibiting activation of the BZLF1 IE promoter (Zp). Furthermore, we find that another p63 gene splice variant, TAp63α, which is expressed in some Burkitt and diffuse large B cell lymphomas, also represses EBV lytic reactivation. We demonstrate that ΔNp63α inhibits the Z promoter indirectly by preventing the ability of other transcription factors, including the viral IE R protein and the cellular KLF4 protein, to activate Zp. Mechanistically, we show that ΔNp63α promotes viral latency in undifferentiated epithelial cells both by enhancing expression of a known Zp repressor protein, c-myc, and by decreasing cellular p38 kinase activity. Furthermore, we find that the ability of cis-platinum chemotherapy to degrade ΔNp63α contributes to the lytic-inducing effect of this agent in EBV-infected epithelial cells. Together these findings demonstrate that the loss of ΔNp63α expression, in conjunction with enhanced expression of differentiation-dependent transcription factors such as BLIMP1 and KLF4, induces lytic EBV reactivation during normal epithelial cell differentiation. Conversely, expression of ΔNp63α in undifferentiated nasopharyngeal carcinoma cells and TAp63α in Burkitt lymphoma promotes EBV latency in these malignancies.
Highlights
Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects over 90% of the human population by adulthood and causes the clinical syndrome, infectious mononucleosis
This study demonstrates that the cellular transcription factor ΔNp63α, which is expressed in undifferentiated basal epithelial cells and is over-expressed in nasopharyngeal carcinoma (NPC) tumors, maintains EBV latency by inhibiting the activity of the viral immediate-early (IE) promoter (Zp) that drives expression of the BZLF1 IE protein
We show the cellular transcription factors KLF4 and BLIMP1, which are preferentially expressed in differentiated epithelial cells, synergistically activate the Z, R, and LMP1 EBV promoters, at least partly explaining why EBV reactivation is induced by epithelial cell differentiation [15,16,36,40,41]
Summary
Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects over 90% of the human population by adulthood and causes the clinical syndrome, infectious mononucleosis. EBV can infect host cells in either latent or lytic forms and persists in the host for life. The virus expresses only a small subset of viral genes and replicates once per cell cycle using the host cell DNA polymerase. The full viral gene complement is expressed, the virus is replicated using the virally-encoded DNA polymerase and infectious virions are produced. The major site of persistent latent EBV infection in humans is memory B cells, the lytic form of infection can be induced by B-cell receptor stimulation, plasma cell differentiation or various other stimuli in B cells [2,3,4,5,6]
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