Targeting human herpesvirus-8 for treatment of Kaposi??s sarcoma and primary effusion lymphoma

Klass, Carmen M.; Offermann, Margaret K.

doi:10.1097/01.cco.0000172823.01190.6c

Cited by 53 publications

(36 citation statements)

References 115 publications

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“…The degree to which antiviral agents specific for HHV8 might play a role in prevention and treatment of KS is being explored. Ganciclovir used to treat cytomegalovirus disease in patients with AIDS decreases the risk of KS but does not achieve the responses in established disease that have been observed in multicentric Castlemen's disease, which is an HHV8-associated lymphoproliferative disorder [11]. This is probably because most cells are latently infected and do not support lytic replication.…”

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confidence: 75%

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Kaposi sarcoma: The African HIV epidemic's partner in crime

Davidson

2010

Pediatric Blood & Cancer

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confidence: 75%

“…This is probably because most cells are latently infected and do not support lytic replication. Valproate may be able to induce lytic replication rendering KS amenable to antiviral therapy [11].…”

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confidence: 99%

Kaposi sarcoma: The African HIV epidemic's partner in crime

Davidson

2010

Pediatric Blood & Cancer

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“…Our studies of the differential activities of SCFAs and MCFAs as inducers or inhibitors of viral reactivation have implications for oncolytic strategies. The HDAC inhibitors butyrate, phenylbutyrate, and VPA have been investigated as lytic activators in cells, mice, and patients (31,(85)(86)(87)(88)(89). One risk of applying lytic induction therapy is that incomplete inhibition of viral replication by antiviral drugs could allow secondary infection and disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…MS-275 and apicidin, representing two additional classes of HDAC inhibitors, and suberoylanilide hydroxamic acid (SAHA) reactivated EBV in HH514-16 cells; this activity was also inhibited by VPA (29). Conversely, VPA is a strong inducer of the lytic cycle of KSHV (29)(30)(31). Since butyrate is a 4-carbon straight-chain fatty acid and VPA is an 8-carbon branched-chain fatty acid, we evaluated the parameters of chain length and branching in lytic activation and repression.…”

Section: Importancementioning

confidence: 99%

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

Gorres

Daigle

Mohanram

et al. 2014

J Virol

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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.

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“…Buger and colleagues were able to inhibit clonal growth of PEL in vitro and in animal models by using antibodies to IL-6 (29). Future approaches may include silencing the LANA-1 gene with small RNA transcripts or using RNA interference to inhibit viral cyclin or viral FLICE inhibitory protein (30,31).…”

Section: Discussionmentioning

confidence: 99%