Abstract
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.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), named human herpesvirus 8 (HHV-8), is the etiologic agent of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD) [1,2,3]
As a major oncogenic human herpesviruses, KSHV infection causes several cancers mostly seen in immunocompromised patients
We screened an Food and Drug Administration (FDA)-approved drug library and identified 15 new anti-KSHV agents. Several of these candidates target histamine receptors, implying the involvement of histamine-related signaling in lytic replication and reactivation of KSHV
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), named human herpesvirus 8 (HHV-8), is the etiologic agent of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD) [1,2,3]. KS is an endothelial-originated multicentric malignant neoplasm found in immunosuppressed patients, and most frequently in patients infected with HIV [1,4]. PEL is a rare and aggressive B-cell non-Hodgkin’s lymphoma that typically presents as a lymphomatous effusion without forming a solid mass [5]. Current therapeutics for KSHV-associated malignancies are not completely efficacious and have significant adverse side effects [7,8]. The identification of more effective and safer anti-KSHV agents is urgently needed
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