Berberine in Human Oncogenic Herpesvirus Infections and Their Linked Cancers.

Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed.

Antiviral Activities of Quercetin and Isoquercitrin Against Human Herpesviruses.

We previously reported that the ethyl acetate (EtOAc) fraction of a 70% ethanol extract of Elaeocarpus sylvestris (ESE) inhibits varicella-zoster virus (VZV) and human cytomegalovirus (HCMV) replication in vitro. PGG (1,2,3,4,6-penta-O-galloyl-ß-D-glucose) is a major chemical constituent of the EtOAc fraction of ESE that inhibits VZV but not HCMV replication. In this study, we comprehensively screened the chemical compounds identified in the EtOAc fraction of ESE for potential antiviral properties. Among the examined compounds, quercetin and isoquercitrin displayed potent antiviral activities against both VZV and HCMV with no significant cytotoxic effects. Both compounds strongly suppressed the expression of VZV and HCMV immediate-early (IE) genes. Our collective results indicated that, in addition to PGG, quercetin and isoquercitrin are bioactive compounds in the EtOAc fraction of ESE that effectively inhibit human herpesvirus replication.

CRISPR/Cas9, a powerful tool to target human herpesviruses.

Over 90% of the adult population is infected with one or multiple herpesviruses. These viruses are characterized by their ability to establish latency, where the host is unable to clear the invader from infected cells resulting in a lifelong infection. Herpesviruses cause a wide variety of (recurrent) diseases such as cold sores, shingles, congenital defects and several malignancies. Although the productive phase of a herpesvirus infection can often be efficiently limited by nucleoside analogs, these drugs are ineffective during a latent herpesvirus infection and are therefore unable to clear herpesviruses from the human host. Advances in genome engineering using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 facilitates virus research and may hold potential to treat or cure previously incurable herpesvirus infections by directly targeting these viruses within infected cells. Here, we review recent applications of the CRISPR/Cas9 system for herpesviral research and discuss the therapeutic potential of the system to treat, or even cure, productive and latent herpesviral infections.

Novel heparan sulfate-binding peptides for blocking herpesvirus entry.

Human cytomegalovirus (HCMV) infection can lead to congenital hearing loss and mental retardation. Upon immune suppression, reactivation of latent HCMV or primary infection increases morbidity in cancer, transplantation, and late stage AIDS patients. Current treatments include nucleoside analogues, which have significant toxicities limiting their usefulness. In this study we screened a panel of synthetic heparin-binding peptides for their ability to prevent CMV infection in vitro. A peptide designated, p5+14 exhibited ~ 90% reduction in murine CMV (MCMV) infection. Because negatively charged, cell-surface heparan sulfate proteoglycans (HSPGs), serve as the attachment receptor during the adsorption phase of the CMV infection cycle, we hypothesized that p5+14 effectively competes for CMV adsorption to the cell surface resulting in the reduction in infection. Positively charged Lys residues were required for peptide binding to cell-surface HSPGs and reducing viral infection. We show that this inhibition was not due to a direct neutralizing effect on the virus itself and that the peptide blocked adsorption of the virus. The peptide also inhibited infection of other herpesviruses: HCMV and herpes simplex virus 1 and 2 in vitro, demonstrating it has broad-spectrum antiviral activity. Therefore, this peptide may offer an adjunct therapy for the treatment of herpes viral infections and other viruses that use HSPGs for entry.

Herpesvirus infections of laboratory macaques.

Non-human primates (NHPs), primarily macaques, are commonly used as non-rodent species in pre-clinical safety assessment studies. The use of macaques in such studies is increasing largely due to the development of biopharmaceutical and immunomodulatory therapies that necessitates extensive safety testing. Macaques, commonly available for use in such studies, are infected by a rich flora of herpesviruses that cause persistent, latent, life-long infections. Primary infection of immune competent macaques is typically subclinical with very little associated morbidity and mortality only in very rare cases. A life-long consequence of herpesvirus infection is periodic stochastic and frequently asymptomatic recurrences from latency throughout an infected macaque's lifetime. With immune modulation or suppression, however, immune control of herpesvirus infections can be lost, resulting in significant disease and even death of the affected animals. Since macaques undergo primary infection with herpesviruses starting around 4-6 months-of-age when maternally-derived antibody begins to wane, it is difficult and costly to derive animals that are herpesvirus-free. Further, the herpesvirus flora and prevalence of infection in laboratory macaques mirrors that of the adult human population making the herpesvirus-infected macaque a reasonable model of the general human population. This review is intended to familiarize toxicologists performing preclinical drug safety studies with the basic biology, disease pathogenesis and consequences of immune suppression in herpesvirus-infected laboratory macaques.

[Experimental myocardiopathy caused by the herpesvirus]. / Eksperimental'naia miokardiopatiia, vyzvannaia virusom gerpesa.

Mice weighing 18--20 g were inoculated with herpes simplex virus type I. The rate of pathological changes in the myocardium was found to depend on the route of virus inoculation and the time of heart examinations in the infected animals. The development of myocardiopathies was not determined by the virus dose used in the test. An immunosuppressant drug, imurane, reduced the rate of heart affections. Pathomorphological changes in the heart were of parenchymatous-interstitial nature, with the leading role of lesions of myocardium muscle cells proper and secondary development of microcirculation disorders. The rate of heart lesions increased when herpes and influenza viruses were given to mice simultaneously; staphylococcus toxin had the same effect.