Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Abstract

H uman herpesviruses are enveloped viruses containing relatively large, double-stranded DNA genomes. Although all herpesviruses experience both latent and lytic stages of infection, they are grouped into three separate families (alpha-, beta-, and gammaherpesviruses) according to differences in sequence homology and cellular tropisms. The alphaherpesviruses, which comprise herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), cause recurrent skin lesions and meningitis (1, 2). Human cytomegalovirus (HCMV), human herpesviruses 6A and 6B (HHV6), and human herpesvirus 7 (HHV7) are betaherpesviruses, which cause severe disease in patients with compromised immune function (3, 4). The gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), which are causally associated with mononucleosis (EBV) as well as a variety of human cancers (5, 6).Each of the eight human herpesviruses encodes a protein kinase (PK) with discernible homology in amino acid sequences and positional similarity in their respective viral genomes. These related protein kinases, termed the conserved herpesvirus protein kinases (CHPKs), are important for viral replication and infection (7-13). They play important roles in multiple processes, including gene expression (8,11,14), viral DNA replication (11,(15)(16)(17), capsid nuclear egress (7,11,18,19), and the DNA damage response (20, 21). For example, EBV PK (the product of the BGLF4 gene) phosphorylates a number of different viral and cellular proteins, including the viral DNA polymerase processivity factor BMRF1 (7,(22)(23)(24); the latent viral proteins EBNA1 (25), EBNA2 (26), and EBNA LP (27); the EBV immediate early (IE) protein BZLF1 (28); the cell cycle regulatory proteins p27 (29) and pRB (30); nuclear lamin A/C (7, 31); and interferon regulatory factor 3 (IRF3) (32). In addition, EBV PK may upregulate the expression of two viral proteins important for nuclear egress, BFRF1 and BFLF2 (11,33). Both EBV PK and the homologous HCMV kinase, UL97, greatly enhance but are not absolutely required for the release of infectious viral particles in vitro and appear to be intimately involved in the pathogenesis associated with viral infections in vivo (34,35). Although maribavir, an inhibitor of HCMV UL97, failed a phase III clinical trial in bone marrow transplant patients (36) (possibly due to insufficient dosing), CHPKs nevertheless remain very promising targets for development of novel antiviral therapeutics.Two guanine nucleoside analogues, ganciclovir (GCV) and acyclovir (ACV), have been used frequently to inhibit replication of various human herpesviruses by targeting viral DNA polymerases (37-40). UL97 mediates the first step of GCV and ACV phosphorylation (41-43). Since the triphosphorylated forms of GCV and ACV are much better substrates for herpesvirus DNA polymerases than cellular DNA polymerases, GCV and ACV inhibit viral DNA replication more effectively than cellular DNA replication (44,45). It was recently found that EBV PK is req...

Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs

“…Moreover, it has been shown that Hsp90 and the PI3K/Akt pathway are critical for replication of CMV and survival of EBV-infected cells [79,80]. These findings further underscore our assumption that an anti-aGvHD strategy with combined Hsp90/PI3K/Akt inhibition might provide an additional protection against opportunistic infections and probably spare, for the most part, the GvI effect.…”

“…Furthermore, it has been demonstrated that Hsp90 inhibitors have strong antifungal activity by preventing the emergence of resistance against echinocandin and azole drugs, 2 classes of antifungal drugs that are widely used for treatment against C. albicans and A. fumigatus infection [77,78]. Moreover, it has been shown that Hsp90 and the PI3K/Akt pathway are critical for replication of CMV and survival of EBV-infected cells [79,80]. These findings further underscore our assumption that an anti-aGvHD strategy with combined Hsp90/PI3K/Akt inhibition might provide an additional protection against opportunistic infections and probably spare, for the most part, the GvI effect.…”

Human cytomegalovirus microRNA miR-US25-1-5p inhibits viral replication by targeting multiple cellular genes during infection

“…In addition, the expression of the EBV-encoded and HCMV-encoded kinases is markedly decreased in EBV-infected and HCMV-infected cells, respectively, when treated with 17-DMAG. Furthermore, 17-DMAG reduces production in Epstein-Barr virus-infected cells (Sun et al, 2013). Based on the studies above, we can speculate that all four of the cellular genes identified in our study may play important roles during virus infection, and may impact virus replication directly or indirectly.…”

HSP90 Protects the Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Oncoprotein from Proteasomal Degradation To Support NF-κB Activation and HTLV-1 Replication

“…Other viral proteins such as the herpes simplex virus 1 (HSV-1) polymerase and Kaposi's sarcoma herpesvirus (KSHV) LANA have also been shown to be localized in the nucleus together with HSP90 (39,40). Indeed, there are an abundance of viral proteins that utilize HSP90 for proper folding, stabilization, and/or trafficking; thus, HSP90 inhibitors represent a potent new class of antiviral drugs with activity against a broad range of viruses, including influenza, hepatitis, and herpesviruses (63)(64)(65). Our results using chronically infected HTLV-1-producing cell lines and proviral clones indicate that HTLV-1 replication is also blocked by HSP90 inhibition.…”