Early inhibitors of human cytomegalovirus: State-of-art and therapeutic perspectives

Mercorelli, Beatrice; Lembo, David; Palù, Giorgio; Loregian, Arianna

doi:10.1016/j.pharmthera.2011.04.007

Cited by 36 publications

(44 citation statements)

References 282 publications

(287 reference statements)

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“…This virus is medically important, causing congenital infection with lifelong disabilities resulting from neurological damage (1)(2)(3), as well as significant life-threatening disease in immunocompromised individuals (4). Productive infection occurs in a wide range of cell types in vivo and in vitro, including fibroblasts and epithelial and endothelial cells.…”

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confidence: 99%

MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

Liu

et al. 2015

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily manifesting as neurological disorders. HCMV infection alters expression of cellular microRNAs (miRs These results suggest that Cdc25a promotes HCMV replication and elevation of Cdc25a levels after HCMV infection are due in part to HCMV-mediated repression of miR-21. Thus, miR-21 is an intrinsic antiviral factor that is modulated by HCMV infection. This suggests a role for miR-21 downregulation in the neuropathogenesis of HCMV infection of the developing CNS. IMPORTANCEHuman cytomegalovirus (HCMV) is a ubiquitous pathogen and has very high prevalence among population, especially in China, and congenital HCMV infection is a major cause for birth defects. Elucidating virus-host interactions that govern HCMV replication in neuronal cells is critical to understanding the neuropathogenesis of birth defects resulting from congenital infection. In this study, we confirm that HCMV infection downregulates miR-21 but upregulates Cdc25a. Further determined the negative effects of cellular miRNA miR-21 on HCMV replication in neural progenitor/stem cells and U-251MG glioblastoma/astrocytoma cells. More importantly, our results provide the first evidence that miR-21 negatively regulates HCMV replication by targeting Cdc25a, a vital cell cycle regulator. We further found that viral gene products of IE1, pp71, and UL26 play roles in inhibiting miR-21 expression, which in turn causes increases in Cdc25a and benefits HCMV replication. Thus, miR-21 appears to be an intrinsic antiviral factor that represents a potential target for therapeutic intervention.

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MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

Liu

et al. 2015

J Virol

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“…Studies of human cytomegalovirus (HCMV) nuclear egress are of particular interest, because of the medical importance of HCMV. HCMV, a betaherpesvirus, causes widespread and lifelong infections that can result in severe diseases in immunocompromised hosts, such as transplant recipients and AIDS patients (4,5), and developmental and hearing disabilities in infants (6). Current anti-HCMV drugs are limited by acute and long-term toxicities, poor oral bioavailability, and/or the emergence of resistance, leading to an urgent need for new antiviral strategies (5,7).…”

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confidence: 99%

“…HCMV, a betaherpesvirus, causes widespread and lifelong infections that can result in severe diseases in immunocompromised hosts, such as transplant recipients and AIDS patients (4,5), and developmental and hearing disabilities in infants (6). Current anti-HCMV drugs are limited by acute and long-term toxicities, poor oral bioavailability, and/or the emergence of resistance, leading to an urgent need for new antiviral strategies (5,7). The process of HCMV nuclear egress could be an attractive target for development of specific antiviral therapy, especially given its importance for HCMV replication and features that differ from a cellular process that resembles nuclear egress events (8,9).…”

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Human Cytomegalovirus UL97 Phosphorylates the Viral Nuclear Egress Complex

Sharma

Bender

Kamil

et al. 2015

J Virol

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Herpesvirus nucleocapsids exit the host cell nucleus in an unusual process known as nuclear egress. The human cytomegalovirus (HCMV) UL97 protein kinase is required for efficient nuclear egress, which can be explained by its phosphorylation of the nuclear lamina component lamin A/C, which disrupts the nuclear lamina. We found that a dominant negative lamin A/C mutant complemented the replication defect of a virus lacking UL97 in dividing cells, validating this explanation. However, as complementation was incomplete, we investigated whether the HCMV nuclear egress complex (NEC) subunits UL50 and UL53, which are required for nuclear egress and recruit UL97 to the nuclear rim, are UL97 substrates. Using mass spectrometry, we detected UL97-dependent phosphorylation of UL50 residue S216 (UL50-S216) and UL53-S19 in infected cells. Moreover, UL53-S19 was specifically phosphorylated by UL97 in vitro. Notably, treatment of infected cells with the UL97 inhibitor maribavir or infection with a UL97 mutant led to a punctate rather than a continuous distribution of the NEC at the nuclear rim. Alanine substitutions in both UL50-S216 and UL53-S19 resulted in a punctate distribution of the NEC in infected cells and also decreased virus production and nuclear egress in the absence of maribavir. These results indicate that UL97 phosphorylates the NEC and suggest that this phosphorylation modulates nuclear egress. Thus, the UL97-NEC interaction appears to recruit UL97 to the nuclear rim both for disruption of the nuclear lamina and phosphorylation of the NEC. IMPORTANCEHuman cytomegalovirus (HCMV) causes birth defects and it can cause life-threatening diseases in immunocompromised patients. HCMV assembles in the nucleus and then translocates to the cytoplasm in an unusual process termed nuclear egress, an attractive target for antiviral therapy. A viral enzyme, UL97, is important for nuclear egress. It has been proposed that this is due to its role in disruption of the nuclear lamina, which would otherwise impede nuclear egress. In validating this proposal, we showed that independent disruption of the lamina can overcome a loss of UL97, but only partly, suggesting additional roles for UL97 during nuclear egress. We then found that UL97 phosphorylates the viral nuclear egress complex (NEC), which is essential for nuclear egress, and we obtained evidence that this phosphorylation modulates this process. Our results highlight a new role for UL97, the mutual dependence of the viral NEC and UL97 during nuclear egress, and differences among herpesviruses. Herpesviruses replicate and package their DNA genomes into capsids in the nucleus of the host cell. The nucleocapsids are then transported out of the nucleus through an unusual process called nuclear egress. A widely accepted model for nuclear egress entails envelopment and de-envelopment of capsids as they transit the nuclear membranes (reviewed in references 1, 2, and 3). Studies of human cytomegalovirus (HCMV) nuclear egress are of particular interest, because of the medical ...

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“…For all these reasons, there is still a strong need to develop new, safe, and effective antiviral compounds, possibly endowed with a new mechanism of action (6). In this regard, the identification of the viral factors that regulate the very early virus-host cell interactions as well as the functional characterization of the first viral proteins expressed in infected cells, such as the pivotal immediate-early 2 (IE2) protein, may now provide a rationale for the design of alternative antiviral strategies (7)(8)(9).…”

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confidence: 99%

The 6-Aminoquinolone WC5 Inhibits Different Functions of the Immediate-Early 2 (IE2) Protein of Human Cytomegalovirus That Are Essential for Viral Replication

Mercorelli

Luganini

Muratore

et al. 2014

Antimicrob Agents Chemother

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The human cytomegalovirus (HCMV) immediate-early 2 (IE2) protein is a multifunctional factor essential for viral replication. IE2 modulates both viral and host gene expression, deregulates cell cycle progression, acts as an immunomodulator, and antagonizes cellular antiviral responses. Based on these facts, IE2 has been proposed as an important target for the development of innovative antiviral approaches. We previously identified the 6-aminoquinolone WC5 as a promising inhibitor of HCMV replication, and here, we report the dissection of its mechanism of action against the viral IE2 protein. Using glutathione S-transferase (GST) pulldown assays, mutagenesis, cell-based assays, and electrophoretic mobility shift assays, we demonstrated that WC5 does not interfere with IE2 dimerization, its interaction with TATA-binding protein (TBP), and the expression of a set of cellular genes that are stimulated by IE2. On the contrary, WC5 targets the regulatory activity exerted by IE2 on different responsive viral promoters. Indeed, WC5 blocked the IE2-dependent negative regulation of the major immediate-early promoter by preventing IE2 binding to the crs element. Moreover, WC5 reduced the IE2-dependent transactivation of a series of indicator constructs driven by different portions of the early UL54 gene promoter, and it also inhibited the transactivation of the murine CMV early E1 promoter by the IE3 protein, the murine cytomegalovirus (MCMV) IE2 homolog. In conclusion, our results indicate that the overall anti-HCMV activity of WC5 depends on its ability to specifically interfere with the IE2-dependent regulation of viral promoters. Importantly, our results suggest that this mechanism is conserved in murine CMV, thus paving the way for further preclinical evaluation in an animal model.

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Early inhibitors of human cytomegalovirus: State-of-art and therapeutic perspectives

Cited by 36 publications

References 282 publications

MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

Human Cytomegalovirus UL97 Phosphorylates the Viral Nuclear Egress Complex

The 6-Aminoquinolone WC5 Inhibits Different Functions of the Immediate-Early 2 (IE2) Protein of Human Cytomegalovirus That Are Essential for Viral Replication

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