Lytic Induction Therapy against Epstein–Barr Virus-Associated Malignancies: Past, Present, and Future

Yiu, Stephanie Pei Tung; Dorothea, Mike; Hui, Kwai Fung; Chiang, Alan Kwok Shing

doi:10.3390/cancers12082142

Cited by 26 publications

(23 citation statements)

References 173 publications

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“…An interesting potential therapeutic strategy could be that of modulating anti-EBV response. This approach has been investigated mainly in the setting of EBV-associated cancer, with the rationale of exploiting EBV presence in tumor cells to target them selectively [ 197 , 198 ]; however, it could also open new perspectives on AIDs.…”

Section: Future Perspectivesmentioning

confidence: 99%

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Quaglia

Merlotti

Andrea

et al. 2021

Viruses

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A causal link between viral infections and autoimmunity has been studied for a long time and the role of some viruses in the induction or exacerbation of systemic lupus erythematosus (SLE) in genetically predisposed patients has been proved. The strength of the association between different viral agents and SLE is variable. Epstein–Barr virus (EBV), parvovirus B19 (B19V), and human endogenous retroviruses (HERVs) are involved in SLE pathogenesis, whereas other viruses such as Cytomegalovirus (CMV) probably play a less prominent role. However, the mechanisms of viral–host interactions and the impact of viruses on disease course have yet to be elucidated. In addition to classical mechanisms of viral-triggered autoimmunity, such as molecular mimicry and epitope spreading, there has been a growing appreciation of the role of direct activation of innate response by viral nucleic acids and epigenetic modulation of interferon-related immune response. The latter is especially important for HERVs, which may represent the molecular link between environmental triggers and critical immune genes. Virus-specific proteins modulating interaction with the host immune system have been characterized especially for Epstein–Barr virus and explain immune evasion, persistent infection and self-reactive B-cell “immortalization”. Knowledge has also been expanding on key viral proteins of B19-V and CMV and their possible association with specific phenotypes such as antiphospholipid syndrome. This progress may pave the way to new therapeutic perspectives, including the use of known or new antiviral drugs, postviral immune response modulation and innate immunity inhibition. We herein describe the state-of-the-art knowledge on the role of viral infections in SLE, with a focus on their mechanisms of action and potential therapeutic targets.

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Section: Future Perspectivesmentioning

confidence: 99%

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Quaglia

Merlotti

Andrea

et al. 2021

Viruses

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“…In tumors, latency gene expression predominates and there is little or no expression of the viral proteins associated with virion production. While some have argued that lytic gene expression plays an important role in the transformation and maintenance of malignancy, others have argued that pharmacologic induction of viral lytic gene expression might be a therapeutic strategy to treat these cancers [ 3 , 4 , 5 ]. EBV reactivation may also be important in a variety of chronic diseases [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Arsenicals, the Integrated Stress Response, and Epstein–Barr Virus Lytic Gene Expression

Lee

Stone

Desai

et al. 2021

Viruses

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Following our observation that clofoctol led to Epstein–Barr virus (EBV) lytic gene expression upon activation of the integrated stress response (ISR), we decided to investigate the impact of As2O3 on viral lytic gene expression. As2O3 has also been reported to activate the ISR pathway by its activation of the heme-regulated inhibitor (HRI). Our investigations show that As2O3 treatment leads to eIF2α phosphorylation, upregulation of ATF4 and TRB3 expression, and an increase of EBV Zta gene expression in lymphoid tumor cell lines as well as in naturally infected epithelial cancer cell lines. However, late lytic gene expression and virion production were blocked after arsenic treatment. In comparison, a small molecule HRI activator also led to increased Zta expression but did not block late lytic gene expression, suggesting that As2O3 effects on EBV gene expression are also mediated through other pathways.

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“…In this strategy, virus transcription, protein expression, and virion production are activated through immune‐mediated clearance, potentially triggering cytolysis of latency reversing agents 11,12 . Furthermore, the Epstein–Barr virus (EBV) lytic cycle can be induced to counter malignancies 13,14 . Mechanistically, the chemical inducers are first used to induce EBV lytic replication, then nucleoside analog antiviral pro‐drugs to kill EBV‐positive cells 15,16 .…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Furthermore, the Epstein-Barr virus (EBV) lytic cycle can be induced to counter malignancies. 13,14 Mechanistically, the chemical inducers are first used to induce EBV lytic replication, then nucleoside analog antiviral pro-drugs to kill EBV-positive cells. 15,16 This mechanism brings us inspirations in the treatment of Kaposi's sarcoma-associated herpesvirus (KSHV)-associated cancers.…”

Section: Introductionmentioning

confidence: 99%

vFLIP‐regulated competing endogenous RNA (ceRNA) networks targeting lytic induction for KSHV‐associated malignancies

Sheng

Chen

et al. 2022

Journal of Medical Virology

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Kaposi's sarcoma‐associated herpesvirus (KSHV) causes life‐long latent infection and malignancies, including KS commonly found in AIDS patients. Lytic replication can be induced to kill tumor cells harboring latent KSHV, through viral cytopathic effects and the subsequent antiviral immune responses. Viral FLICE‐inhibitory protein (vFLIP), encoded by KSHV ORF K13, inhibits KSHV lytic reactivation, implying that the competing endogenous RNA (ceRNA) networks regulated by vFLIP can be modulated to induce the lytic reactivation of latent KSHV, a promising strategy for KSHV‐associated malignancies. Here, we performed whole‐transcriptome sequencing to reveal the global landscape of noncoding RNAs and messenger RNAs (mRNAs) in iSLK‐RGB‐BAC16 cells and iSLK‐RGB‐K13 mutant cells. It showed that vFLIP regulated 227 differentially expressed (DE) long non‐coding RNAs (lncRNAs), 57 DE circular RNAs (circRNAs), 20 DE microRNAs (miRNAs), and 1371 DE mRNAs. Enrichment analysis verified that riboflavin metabolism was simultaneously enriched in DE genes related to miRNAs, lncRNAs, and circRNAs. The upregulated hsa‐miR‐378i and hsa‐miR‐3654, and downregulated miR‐4467, miR‐3163, miR‐4451, and miR‐4257 were significantly enriched in the ceRNA complex network, which contained 9 upregulated and 7 downregulated circRNAs, 5 upregulated and 85 downregulated lncRNAs, 5 upregulated and 35 downregulated mRNAs. Finally, we constructed and validated two vFLIP‐regulated ceRNA networks: circRNA hsa_circ_0070049/hsa‐miR‐378i/SPEG/FOXQ1 and lncRNA AL031123.1/hsa‐miR‐378i/SPEG/FOXQ1. Taken together, the two ceRNA networks may mediate KSHV reactivation. These novel findings refreshed the present understanding of ceRNA network in KSHV lytic induction and provided potential therapeutic targets for KSHV‐associated malignancies.

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Lytic Induction Therapy against Epstein–Barr Virus-Associated Malignancies: Past, Present, and Future

Cited by 26 publications

References 173 publications

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Arsenicals, the Integrated Stress Response, and Epstein–Barr Virus Lytic Gene Expression

vFLIP‐regulated competing endogenous RNA (ceRNA) networks targeting lytic induction for KSHV‐associated malignancies

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