Activation and Repression of Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycles by Short- and Medium-Chain Fatty Acids

Abstract

The lytic cycles of Epstein-Barr virus (EBV) and Kaposi's 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 an 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 concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways. IMPORTANCELytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the 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 the understanding of pathways that control the latent-to-lytic switch and identify naturally occurring molecules that may regulate this process.

Signatures of oral microbiome in HIV-infected individuals with oral Kaposi's sarcoma and cell-associated KSHV DNA

“…Moreover, anti-inflammatory responses can be induced by the generation of regulatory T cells through the production of short-chain fatty acid (SCFA) by bacteria belonging to the clostridia cluster [44][45][46]. Also, and perhaps even more important, SCFA, such as sodium butyrate and valproic acid, that act as histone deacetylase (HDAC) inhibitors, can reactivate KSHV [21,22], and therefore increased butyrate production, might promote KS tumorigenesis through lytic activation of KSHV [47]. Interestingly, HIV-infected individuals with severe periodontal disease display a higher level of SCFA in the saliva compared to healthy individuals [48].…”

“…Numerous pathogenic mechanisms, including the production of genotoxic inducers, the activation of TLRs and pro-inflammatory pathways, the inhibition of the immune response, and the increase of the cellular turnover have been proposed to explain the oncogenic properties of some types of bacteria [15]. Bacterial byproducts such as short-chain fatty acids (SCFA) that are highly abundant in individuals suffering from periodontal disease can induce KSHV reactivation [21,22]. Interestingly, HIV-infected individuals display a higher rate of periodontal disease [23], which has been proposed to promote oral KS development by inducing proinflammatory cytokines or releasing SCFA.…”

Epstein–Barr Virus: Diseases Linked to Infection and Transformation

“…Epstein–Barr virus reactivation can be triggered in human cells by either chemical agents or biological stimuli, including TPA, sodium butyrate, HDAC inhibitors, phorbol esters, calcium ionophores, chemotherapeutic agents, BCR engagement, TGF-β, and hypoxia ( Figure 1 ; Gorres et al, 2014; Kenney and Mertz, 2014). BCR signaling-mediated EBV reactivation is mainly induced through PI3K and PKC that further regulate the activity of the Zp promoter (Goswami et al, 2012).…”

Lipids, lipid metabolism and Kaposi’s sarcoma-associated herpesvirus pathogenesis

“…A recent study has shown that reactivation can be induced by some short-chain fatty acids (SCFAs) such as phenylbutyrate through inhibiting histone deacetylase (HDAC) activities (Gorres et al, 2014). Consistently, Yu et al have found that several SCFAs produced by periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum can also induce the KSHV lytic reactivation by suppressing HDACs as well as two histone N-lysine methyltransferases (HLMTs): enhancer of zeste homo-log2 (EZH2) and suppressor of variegation 3-9 homo-log1 (SUV39H1) (Yu et al, 2014).…”