Activation and repression of Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus lytic cycles by short- and medium-chain fatty acids.

The lytic cycles of Epstein-Barr virus (EBV) and Kaposi
sarcoma-associated herpesvirus (KSHV) are induced in cell culture by
sodium butyrate (NaB), a short-chain fatty acid (SCFA) histone
deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and HDAC
inhibitor, induces the lytic cycle of KSHV, but blocks EBV lytic
reactivation. To explore the hypothesis that structural differences
between NaB and VPA account for their functional effects on the two
related viruses, we investigated the capacity of 16 structurally related
short- and medium-chain fatty acids to promote or prevent lytic cycle
reactivation. SCFAs differentially affected EBV and KSHV reactivation.
KSHV was reactivated by all SCFAs that are HDAC inhibitors, including
phenylbutyrate. However, several fatty acid HDAC inhibitors, such as
isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of
KSHV lytic transcripts could not be blocked completely by any fatty acid
tested. In contrast, several medium-chain fatty acids inhibited lytic
activation of EBV. Fatty acids that blocked EBV reactivation were more
lipophilic than those that activated EBV. VPA blocked activation of the
BZLF1 promoter by NaB, but did not block the transcriptional function of
ZEBRA. VPA also blocked activation of the DNA damage response that
accompanies EBV lytic cycle activation. Properties of SCFAs in addition
to their effects on chromatin are likely to explain activation or
repression of EBV. We conclude that fatty acids stimulate the two
related human gamma-herpesviruses to enter the lytic cycle through
different pathways.


Lytic reactivation of EBV
and KSHV is needed for persistence of the virus and plays a role in
carcinogenesis. Our direct comparison highlights the mechanistic
differences of lytic reactivation between related human oncogenic
gammaherpesviruses. Our findings have therapeutic implications, as fatty
acids are found in the diet and produced by human microbiota. Small
molecule inducers of the lytic cycle are desired for oncolytic therapy.
Inhibition of viral reactivation, alternatively, may prove useful in
cancer treatment. Overall, our findings contribute to understanding
pathways that control the latent to lytic switch and identify naturally
occurring molecules that may regulate this process.

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