scholarly journals Inhibition of polo-like kinase 1 (PLK1) facilitates reactivation of gamma-herpesviruses and their elimination

2021 ◽  
Vol 17 (7) ◽  
pp. e1009764
Author(s):  
Ayan Biswas ◽  
Dawei Zhou ◽  
Guillaume N. Fiches ◽  
Zhenyu Wu ◽  
Xuefeng Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
De Novo ◽  
People Living With Hiv ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Cytopathic Effects ◽  
Lytic Reactivation ◽  
Latently Infected ◽  
Epstein Barr ◽  
Living With Hiv

Both Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) establish the persistent, life-long infection primarily at the latent status, and associate with certain types of tumors, such as B cell lymphomas, especially in immuno-compromised individuals including people living with HIV (PLWH). Lytic reactivation of these viruses can be employed to kill tumor cells harboring latently infected viral episomes through the viral cytopathic effects and the subsequent antiviral immune responses. In this study, we identified that polo-like kinase 1 (PLK1) is induced by KSHV de novo infection as well as lytic switch from KSHV latency. We further demonstrated that PLK1 depletion or inhibition facilitates KSHV reactivation and promotes cell death of KSHV-infected lymphoma cells. Mechanistically, PLK1 regulates Myc that is critical to both maintenance of KSHV latency and support of cell survival, and preferentially affects the level of H3K27me3 inactive mark both globally and at certain loci of KSHV viral episomes. Furthremore, we recognized that PLK1 inhibition synergizes with STAT3 inhibition to efficiently induce KSHV reactivation. We also confirmed that PLK1 depletion or inhibition yields the similar effect on EBV lytic reactivation and cell death of EBV-infected lymphoma cells. Lastly, we noticed that PLK1 in B cells is elevated in the context of HIV infection and caused by HIV Nef protein to favor KSHV/EBV latency.

scholarly journals Inhibition of Polo-like kinase 1 (PLK1) to facilitate the reactivation and elimination of latent gamma-herpesviruses

2020 ◽  
Author(s):  
Ayan Biswas ◽  
Guillaume Fiches ◽  
Dawei Zhou ◽  
Jianwen Que ◽  
Jian Zhu ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
People Living With Hiv ◽  
Barr Virus ◽  
Cytopathic Effects ◽  
Lytic Reactivation ◽  
Latently Infected ◽  
Novel Host ◽  
Epstein Barr ◽  
Living With Hiv

AbstractBoth Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) can establish the persistent, life-long infection primarily at the latent status, and contribute to certain types of tumors, including B cell lymphomas, especially in immuno-compromised individuals, such as people living with HIV (PLWH). Lytic reactivation of these viruses can be employed to kill tumor cells harboring latently infected viral episomes, through the viral cytopathic effects and the subsequent antiviral immune responses. In this study, we identified that expression of Polo-like kinase 1 (PLK1) in B cells is elevated in the context of HIV infection and by HIV Nef protein. We further demonstrated that PLK1 depletion or inhibition can promote KSHV reactivation and cell death of KSHV-reactivated tumor cells. Mechanistically, PLK1 regulates Myc protein that is critical for both maintenance of KSHV latency and support of cell survival, and affects the level of H3K27me3 suppressive mark both globally and at certain loci of KSHV viral episomes. Lastly, we recognized that PLK1 inhibition can synergize with STAT3 inhibition to induce efficient KSHV reactivation. PLK1 depletion or inhibition yielded the similar effect on promoting EBV reactivation and cell death of EBV-reactivated tumor cells. Our findings illustrated that PLK1 is a novel host target that can be inhibited to benefit the viral oncolysis to eliminate KSHV/EBV-infected tumor cells.

scholarly journals Hodgkin Lymphoma in People Living with HIV

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4366
Author(s):  
Jose-Tomas Navarro ◽  
José Moltó ◽  
Gustavo Tapia ◽  
Josep-Maria Ribera
Keyword(s):  
Hodgkin Lymphoma ◽  
Interdisciplinary Collaboration ◽  
Survival Rates ◽  
People Living With Hiv ◽  
Barr Virus ◽  
Non Hodgkin Lymphoma ◽  
Combined Antiretroviral Therapy ◽  
Epstein Barr ◽  
Living With Hiv ◽  
Hiv Negative

Despite widespread use of combined antiretroviral therapy (cART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with cART. While the incidence of aggressive forms of non-Hodgkin lymphoma decreased after the advent of cART, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein–Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching that of the general population. In this regard, effective cART during chemotherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug–drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PLWH with HL. In this article the authors review and update the epidemiological, clinical and biological aspects of HL presenting in PLWH with special emphasis on advances in prognosis and the factors that have contributed to it.

scholarly journals EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 599 ◽  
Author(s):  
Mara Cirone
Keyword(s):  
Immune Response ◽  
Viral Replication ◽  
De Novo ◽  
Antioxidant Response ◽  
Lytic Cycle ◽  
Immune Recognition ◽  
Barr Virus ◽  
Latently Infected ◽  
Epstein Barr

Autophagy is a catabolic process strongly involved in the immune response, and its dysregulation contributes to the onset of several diseases including cancer. The human oncogenic gammaherpesviruses, Epstein—Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), manipulate autophagy, either during the de novo infection or during the lytic reactivation, in naturally latently-infected lymphoma cells. In particular, the gammaherpesvirus infection reduces autophagy in immune cells, such as monocytes, resulting in the impairment of cell survival and cell differentiation into dendritic cells (DCs), which are essential for initiating and regulating the immune response. In the case of EBV, the reduction of autophagy in these cells, leading to p62 accumulation, activated the p62-NRF2-antioxidant response, reducing ROS, and further inhibiting autophagy. KSHV inhibits autophagy in monocytes by de-phosphorylating JNK2, altering the calpains–calpastatin balance and increasing the calpain activity responsible for the cleavage of ATG5. To further impair the immune response, KSHV also inhibits autophagy in differentiated DCs by hyper-phosphorylating STAT3. Conversely, when the lytic cycle is induced in vitro in latently-infected lymphoma B cells, both EBV and KSHV promote autophagy to enhance their replication, although the final autophagic steps are blocked through the down-regulation of Rab7. This strategy allows viruses to avoid the destructive environment of lysosomes, and to exploit the autophagic machinery for intracellular transportation. EBV and KSHV encode for proteins that may either inhibit or promote autophagy and, in addition, they can modulate the cellular pathways that control this process. In this review we will discuss the findings that indicate that autophagy is dysregulated by gammaherpesvirus to promote immune suppression, facilitate viral replication and contribute to the onset and maintenance of gammaherpesvirus-associated malignancies.

scholarly journals Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 450 ◽  
Author(s):  
Abbie G. Anderson ◽  
Cullen B. Gaffy ◽  
Joshua R. Weseli ◽  
Kelly L. Gorres
Keyword(s):  
Atypical Antipsychotic ◽  
Antipsychotic Drug ◽  
Burkitt Lymphoma ◽  
Epstein Barr Virus ◽  
Lytic Cycle ◽  
Lymphoma Cells ◽  
Atypical Antipsychotic Drug ◽  
Barr Virus ◽  
Lytic Reactivation ◽  
Epstein Barr

Epstein–Barr virus (EBV), a member of the Herpesviridae family, maintains a lifelong latent infection in human B cells. Switching from the latent to the lytic phase of its lifecycle allows the virus to replicate and spread. The viral lytic cycle is induced in infected cultured cells by drugs such as sodium butyrate and azacytidine. Lytic reactivation can be inhibited by natural products and pharmaceuticals. The anticonvulsant drugs valproic acid and valpromide inhibit EBV in Burkitt lymphoma cells. Therefore, other drugs that treat neurological and psychological disorders were investigated for effects on EBV lytic reactivation. Clozapine, an atypical antipsychotic drug used to treat schizophrenia and bipolar disorder, was found to inhibit the reactivation of the EBV lytic cycle. Levels of the viral lytic genes BZLF1, BRLF1, and BMLF1 were decreased by treatment with clozapine in induced Burkitt lymphoma cells. The effects on viral gene expression were dependent on the dose of clozapine, yet cells were viable at an inhibitory concentration of clozapine. One metabolite of clozapine—desmethylclozapine—also inhibited EBV lytic reactivation, while another metabolite—clozapine-N-oxide—had no effect. These drugs may be used to study cellular pathways that control the viral lytic switch in order to develop treatments for diseases caused by EBV.

scholarly journals Hodgkin Lymphoma in People Living With HIV

2021 ◽  
Author(s):  
Jose Tomas Navarro ◽  
Jose Moltó ◽  
Gustavo Tapia ◽  
Josep Maria Ribera
Keyword(s):  
Hodgkin Lymphoma ◽  
Interdisciplinary Collaboration ◽  
Survival Rates ◽  
People Living With Hiv ◽  
Barr Virus ◽  
Non Hodgkin Lymphoma ◽  
Combined Antiretroviral Therapy ◽  
Epstein Barr ◽  
Living With Hiv ◽  
Hiv Negative

Despite widespread use of combined antiretroviral therapy (cART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with cART. While incidence of aggressive forms of non-Hodgkin lymphoma decreased after cART advent, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching to that of the general population. In this regard, effective chem-otherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug-drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the op-timal treatment of PLWH with HL. In this article the authors review and update the epidemio-logical, clinical and biological aspects of HL presenting in PLWH with special emphasis in the improvement on prognosis and the factors that have contributed to it.

scholarly journals De Novo Protein Synthesis Is Required for Lytic Cycle Reactivation of Epstein-Barr Virus, but Not Kaposi's Sarcoma-Associated Herpesvirus, in Response to Histone Deacetylase Inhibitors and Protein Kinase C Agonists

2007 ◽  
Vol 81 (17) ◽  
pp. 9279-9291 ◽  
Author(s):  
Jianjiang Ye ◽  
Lyndle Gradoville ◽  
Derek Daigle ◽  
George Miller
Keyword(s):  
Protein Synthesis ◽  
Sodium Butyrate ◽  
De Novo ◽  
Primary Effusion Lymphoma ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Lytic Cycle ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT The oncogenic human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are latent in cultured lymphoma cells. We asked whether reactivation from latency of either virus requires de novo protein synthesis. Using Northern blotting and quantitative reverse transcriptase PCR, we measured the kinetics of expression of the lytic cycle activator genes and determined whether abundance of mRNAs encoding these genes from either virus was reduced by treatment with cycloheximide (CHX), an inhibitor of protein synthesis. CHX blocked expression of mRNAs of EBV BZLF1 and BRLF1, the two EBV lytic cycle activator genes, when HH514-16 Burkitt lymphoma cells were treated with histone deacetylase (HDAC) inhibitors, sodium butyrate or trichostatin A, or a DNA methyltransferase inhibitor, 5-Aza-2′-deoxycytidine. CHX also inhibited EBV lytic cycle activation in B95-8 marmoset lymphoblastoid cells by phorbol ester phorbol-12-myristate-13-acetate (TPA). EBV lytic cycle induction became resistant to CHX between 4 and 6 h after application of the inducing stimulus. KSHV lytic cycle activation, as assessed by ORF50 mRNA expression, was rapidly induced by the HDAC inhibitors, sodium butyrate and trichostatin A, in HH-B2 primary effusion lymphoma cells. In HH-B2 cells, CHX did not inhibit, but enhanced, expression of the KSHV lytic cycle activator gene, ORF50. In BC-1, a primary effusion lymphoma cell line that is dually infected with EBV and KSHV, CHX blocked EBV BRLF1 lytic gene expression induced by TPA and sodium butyrate; KSHV ORF50 mRNA induced simultaneously in the same cells by the same inducing stimuli was resistant to CHX. The experiments show, for the cell lines and inducing agents studied, that the EBV BZLF1 and BRLF1 genes do not behave with “immediate-early” kinetics upon reactivation from latency. KSHV ORF50 is a true “immediate-early” gene. Our results indicate that the mechanism by which HDAC inhibitors and TPA induce lytic cycle gene expression of the two viruses differs and suggest that EBV but not KSHV requires one or more proteins to be newly synthesized between 4 and 6 h after application of an inducing stimulus.

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