Identification of new antiviral agents against Kaposi’s sarcoma-associated herpesvirus (KSHV) by high-throughput drug screening reveals the role of histamine-related signaling in promoting viral lytic reactivation

English version

Autoři: Jungang Chen ^aff001; Lu Dai ^aff001; Alana Goldstein ^aff002; Haiwei Zhang ^aff003; Wei Tang ^aff003; J. Craig Forrest ^aff004; Steven R. Post ^aff001; Xulin Chen ^aff003; Zhiqiang Qin ^aff001
Působiště autorů: Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America ^aff001; Departments of Diagnostic Sciences, School of Dentistry, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America ^aff002; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Hubei, China ^aff003; Department of Microbiology & Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America ^aff004
Vyšlo v časopise: Identification of new antiviral agents against Kaposi’s sarcoma-associated herpesvirus (KSHV) by high-throughput drug screening reveals the role of histamine-related signaling in promoting viral lytic reactivation. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008156
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008156

Souhrn

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several human cancers, such as Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL). Current treatment options for KSHV infection and virus associated diseases are sometimes ineffective, therefore, more effectively antiviral agents are urgently needed. As a herpesvirus, lytic replication is critical for KSHV pathogenesis and oncogenesis. In this study, we have established a high-throughput screening assay by using an inducible KSHV+ cell-line, iSLK.219. After screening a compound library that consisted of 1280 Food and Drug Administration (FDA)-approved drugs, 15 hit compounds that effectively inhibited KSHV virion production were identified, most of which have never been reported with anti-KSHV activities. Interestingly, 3 of these drugs target histamine receptors or signaling. Our data further confirmed that antagonists targeting different histamine receptors (HxRs) displayed excellent inhibitory effects on KSHV lytic replication from induced iSLK.219 or BCBL-1 cells. In contrast, histamine and specific agonists of HxRs promoted viral lytic replication from induced iSLK.219 or KSHV-infected primary cells. Mechanistic studies indicated that downstream MAPK and PI3K/Akt signaling pathways were required for histamine/receptors mediated promotion of KSHV lytic replication. Direct knockdown of HxRs in iSLK.219 cells effectively blocked viral lytic gene expression during induction. Using samples from a cohort of HIV+ patients, we found that the KSHV+ group has much higher levels of histamine in their plasma and saliva than the KSHV- group. Taken together, our data have identified new anti-KSHV agents and provided novel insights into the molecular bases of host factors that contribute to lytic replication and reactivation of this oncogenic herpesvirus.

Klíčová slova:

Drug screening – Histamine – Kaposi's sarcoma-associated herpesvirus – Library screening – MAPK signaling cascades – Saliva – Viral replication – Virions

Zdroje

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