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

Ayan Biswas,Dawei Zhou,Jian Zhu,Guillaume N Fiches,Zhenyu Wu,Qin Ma,Netty G Santoso,Weiqiang Zhao,Xuefeng Liu,Shou-Jiang Gao

doi:10.1371/journal.ppat.1009764

Ayan Biswas, Dawei Zhou + Show 8 more

Open Access

https://doi.org/10.1371/journal.ppat.1009764

Copy DOI

Abstract

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.

Highlights

Kaposi’s sarcoma-associated herpesvirus (KSHV), is an etiological agent of Kaposi’s sarcoma (KS)–a common acquired immunodeficiency syndrome (AIDS)-associated malignancy [1], as well as two lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman’s disease (CAD) [2]
KSHV is a large double-stranded DNA virus belonging to human gamma-herpesviruses and capable of establishing the long-term persistent infection, which causes cancers under immunocompromised states, such as acquired immunodeficiency syndrome (AIDS)
polo-like kinase 1 (PLK1) inhibitors are demonstrated to have promising results to inhibit cell survival of tumor cells vs non-tumor cells [16], and our study suggests that they can be further considered for viral oncolysis approach to treat KSHV/Epstein-barr virus (EBV)-positive B lymphomas in people living with HIV (PLWH), based on the result that PLK1 expression in B cells was induced in the setting of HIV co-infection

Summary

Introduction

Kaposi’s sarcoma-associated herpesvirus (KSHV), is an etiological agent of Kaposi’s sarcoma (KS)–a common AIDS-associated malignancy [1], as well as two lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman’s disease (CAD) [2]. KSHV infection includes latent and lytic phases [5,6]. KSHV establishes latency in most of immunocompetent individuals, primarily in B cells [6]. Such KSHV latently infected B cells constitute a major source of KSHV viral reservoirs to maintain KSHV genomes and propagate new KSHV viruses. Epstein-barr virus (EBV) belongs to the same human γ-herpesvirus family as KSHV, and primarily infect B cells in a latent phase that can be reversed to lytic replication. It is interesting to note that nearly 70% of PEL cell lines are co-infected with EBV. Studies have demonstrated that EBV co-infected PEL cell lines are more tumorigenic compared to the EBV negative ones [7]

Objectives

Methods

Results

Discussion

Conclusion