Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus responsible for the development of Kaposi’s sarcoma, primary effusion lymphoma (PEL), and Multicentric Castleman’s disease in immunocompromised individuals. Despite the burden of these diseases there are few treatment options for afflicted individuals, due in part to our limited understanding of virus-host interactions. Tip60, a histone aceytltransferase (HAT) has been previously shown to interact with both the KSHV latency associated nuclear antigen protein (LANA), which is the main factor in maintaining the viral latent state, and ORF36, a viral kinase expressed in the lytic phase. We further investigated Tip60-virus interaction to ascertain Tip60’s role in the viral life cycle and its potential as a target for future therapeutics. Through modulation of Tip60 expression in HEK293T cells harboring a plasmid containing the KSHV viral episome, Bac36, we found that Tip60 is vital for both lytic replication as well as efficient expression of latent genes. Interestingly, Tip60 small molecule inhibitors, MG149 and NU9056, similarly inhibited latent and lytic genes, and reduced virion production in wild-type KSHV+/EBV- PEL, BCBL-1 cells. Long-term treatment with these Tip60 inhibitors selectively decreased the viability of KSHV-infected B lymphoma cells compared to uninfected cells. From this study, we conclude that Tip60 is important for KSHV infection and its associated cancer development, and Tip60 is therefore a potential target for future antiviral and anticancer therapeutics.
Highlights
Kaposi’s sarcoma (KS) associated herpes virus (KSHV) known as human herpes virus 8 (HHV8) is a γ-herpes virus associated with KS endothelial lesions as well as several lymphoproliferative disorders, including primary effusion lymphoma (PEL) and Multicentric Castleman’s disease (Reddy and Mitsuyasu, 2011; Cesarman, 2014)
To determine if Tip60 is involved in Kaposi’s sarcoma-associated herpesvirus (KSHV) replication we knocked down Tip60 expression in HEK293T.Bac36 cells which were prepared by stably transfecting HEK 293T cells with the KSHV plasmid Bac36, as previously described (Zhou et al, 2002)
In TPA/sodium butyrate (SB) stimulated cells MG149 and NU9056 treatments reduced viral genomes by 33 and 48%, respectively, indicating that inhibiting Tip60 blocks lytic DNA replication (Figure 3H). These results suggest that Tip60 is critical for expression of all three types of KSHV lytic genes, and that Tip60 inhibition using small-molecule compounds can potently affect KSHV lytic replication
Summary
Kaposi’s sarcoma (KS) associated herpes virus (KSHV) known as human herpes virus 8 (HHV8) is a γ-herpes virus associated with KS endothelial lesions as well as several lymphoproliferative disorders, including primary effusion lymphoma (PEL) and Multicentric Castleman’s disease (Reddy and Mitsuyasu, 2011; Cesarman, 2014). These malignancies are most prevalent in immunocompromised individuals, those infected with the human immunodeficiency. Chemotherapy, antiviral drugs, and radiotherapy have been used to treat KS, but are toxic and not completely effective (Coen et al, 2014). Antiviral drugs approved for use against other herpesviruses are being examined for their efficacy against KSHV (Sergerie and Boivin, 2003; Coen et al, 2014)
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