scholarly journals Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 150
Author(s):  
Clotilde Muller ◽  
Sophie Alain ◽  
Thomas F. Baumert ◽  
Gaëtan Ligat ◽  
Sébastien Hantz
Keyword(s):  
Human Cytomegalovirus ◽  
Human Herpesvirus ◽  
Dna Packaging ◽  
Therapeutic Options ◽  
New Drugs ◽  
Capsid Assembly ◽  
Significant Activity ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Capsid Maturation

Herpesviruses are the causative agents of several diseases. Infections are generally mild or asymptomatic in immunocompetent individuals. In contrast, herpesvirus infections continue to contribute to significant morbidity and mortality in immunocompromised patients. Few drugs are available for the treatment of human herpesvirus infections, mainly targeting the viral DNA polymerase. Moreover, no successful therapeutic options are available for the Epstein–Barr virus or human herpesvirus 8. Most licensed drugs share the same mechanism of action of targeting the viral polymerase and thus blocking DNA polymerization. Resistances to antiviral drugs have been observed for human cytomegalovirus, herpes simplex virus and varicella-zoster virus. A new terminase inhibitor, letermovir, recently proved effective against human cytomegalovirus. However, the letermovir has no significant activity against other herpesviruses. New antivirals targeting other replication steps, such as capsid maturation or DNA packaging, and inducing fewer adverse effects are therefore needed. Targeting capsid assembly or DNA packaging provides additional options for the development of new drugs. In this review, we summarize recent findings on capsid assembly and DNA packaging. We also described what is known about the structure and function of capsid and terminase proteins to identify novels targets for the development of new therapeutic options.

scholarly journals Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro

2005 ◽  
Vol 49 (9) ◽  
pp. 3724-3733 ◽  
Author(s):  
Stephanie L. Williams-Aziz ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Shannon L. Daily ◽  
Mark N. Prichard ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
In Vitro Assays ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Lipid Ester ◽  
Epstein Barr ◽  
Simplex Virus

ABSTRACT Cidofovir (CDV) is an effective therapy for certain human cytomegalovirus (HCMV) infections in immunocompromised patients that are resistant to other antiviral drugs, but the compound is not active orally. To improve oral bioavailability, a series of lipid analogs of CDV and cyclic CDV (cCDV), including hexadecyloxypropyl-CDV and -cCDV and octadecyloxyethyl-CDV and -cCDV, were synthesized and found to have multiple-log-unit enhanced activity against HCMV in vitro. On the basis of the activity observed with these analogs, additional lipid esters were synthesized and evaluated for their activity against herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus, murine cytomegalovirus, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8. Using several different in vitro assays, concentrations of drug as low as 0.001 μM reduced herpesvirus replication by 50% (EC50) with the CDV analogs, whereas the cCDV compounds were generally less active. In most of the assays performed, the EC50 values of the lipid esters were at least 100-fold lower than the EC50 values for unmodified CDV or cCDV. The lipid analogs were also active against isolates that were resistant to CDV, ganciclovir, or foscarnet. These results indicate that the lipid ester analogs are considerably more active than CDV itself against HSV, VZV, CMV, EBV, HHV-6, and HHV-8 in vitro, suggesting that they may have potential for the treatment of infections caused by a variety of herpesviruses.

scholarly journals In Vitro Activities of Benzimidazole d- and l-Ribonucleosides against Herpesviruses

2003 ◽  
Vol 47 (7) ◽  
pp. 2186-2192 ◽  
Author(s):  
Stephanie L. Williams ◽  
Caroll B. Hartline ◽  
Nicole L. Kushner ◽  
Emma A. Harden ◽  
Deborah J. Bidanset ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Human Herpesvirus ◽  
Significant Activity ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Culture Cells ◽  
Simplex Virus ◽  
Human Cmv ◽  
Hsv 1

ABSTRACT Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and human herpesvirus 8 (HHV-8) are responsible for a number of clinical manifestations in both normal and immunocompromised individuals. The parent benzimidazole ribonucleosides evaluated in this series, 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole (BDCRB) and maribavir (1263W94), are potent and selective inhibitors of human CMV replication. These nucleosides act by two different mechanisms. BDCRB blocks the processing and maturation of viral DNA, whereas 1263W94 inhibits the viral enzyme pUL97 and interferes with DNA synthesis. In the present study, we have evaluated the in vitro antiviral activity of BDCRB, an analog, GW275175X (175X), and 1263W94 against the replication of HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, and HHV-8. By using various methodologies, significant activity was observed against human CMV and EBV but not against HSV-1, HSV-2, VZV, HHV-6, or HHV-8. Plaque reduction assays performed on a variety of laboratory and clinical isolates of human CMV indicated that all strains, including those resistant to ganciclovir (GCV) and foscarnet, were sensitive to all three benzimidazole ribonucleosides, with mean 50% effective concentration values of about 1 to 5 μM compared to that of GCV at 6 μM. The toxicity of these compounds in tissue culture cells appeared to be similar to that observed with GCV. These results demonstrate that the benzimidazole ribonucleosides are active against human CMV and EBV and suggest that they may be useful for the treatment of infections caused by these herpesviruses.

scholarly journals Recent Developments in Viral Load Measurements in Human Herpesviruses

1999 ◽  
Vol 10 (suppl c) ◽  
pp. 33C-40C
Author(s):  
Guy Boivin
Keyword(s):  
Clinical Utility ◽  
Biological Fluids ◽  
Quantitative Polymerase Chain Reaction ◽  
Human Herpesvirus ◽  
Relevant Information ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Recent Developments ◽  
Simplex Virus ◽  
Human Herpesviruses

Recent developments in molecular biology have allowed precise quantitative analysis of herpesvirus DNA in many biological fluids. Th is paper reviews the clinical utility of performing quantitative polymerase chain reaction testing for herpesviruses. In particular, the assessment of the cytomegalovirus (CMV) DNA load in blood with regard to the development of CMV disease in immunocompromised patients is discussed in greater detail. Relevant information exists to support measuring the CMV burden in the blood of AIDS and transplant patients for diagnostic and treatment monitoring purposes, and, to a lesser extent, to envision the monitoring of the circulating Epstein-Barr virus load for the prevention of pose-transplant lymphoproliferative disorders. On the ocher hand, there are controversial data on the clinical utility of measuring the herpes simplex virus (HSV) load in cerebrospinal fluid of patients with HSV encephalitis and on the relationship between the human herpesvirus 8 DNA load in diverse biological fluids and the presence of Kaposi's sarcoma. There is a paucity of information about the clinical impact of quantifying the other human herpesviruses (varicella-zoster virus, and human herpesviruses 6 and 7).

scholarly journals Association of infections with multiple sclerosis in Gulf Cooperation Council countries: a review

2019 ◽  
Vol 48 (4) ◽  
pp. 030006051988415
Author(s):  
O Al Wutayd
Keyword(s):  
Multiple Sclerosis ◽  
Arabian Gulf ◽  
Human Herpesvirus ◽  
Epidemiological Studies ◽  
Gulf Cooperation Council ◽  
Gulf Region ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Serological Studies ◽  
Epstein Barr

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system, causing inflammation, demyelination, and neurodegeneration. Infection can play a role in its etiology. Herein, a review is presented of studies that have reported an association between infection and MS risk in countries of the Arabian Gulf region. Searches of the PubMed, Google Scholar, and Science Direct databases were carried out using various search terms, and relevant studies published through January 2019 on the epidemiology of MS in Gulf Cooperation Council countries identified. MS has been found to be associated with measles in Saudi Arabia and Epstein–Barr virus in Kuwait whereas no association has been identified between risk of MS and varicella-zoster virus, mumps, or human herpesvirus-6. However, few epidemiological studies on this topic have been conducted in countries of the Gulf region. Longitudinal and serological studies to establish robust evidence between infection and risk of MS are highly recommended, and a regional MS registry is needed.

scholarly journals Atomic structure of the human herpesvirus 6B capsid and capsid-associated tegument complexes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yibo Zhang ◽  
Wei Liu ◽  
Zihang Li ◽  
Vinay Kumar ◽  
Ana L. Alvarez-Cabrera ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Atomic Structure ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Capsid Assembly ◽  
High Similarity ◽  
Tegument Proteins ◽  
Atomic Structures ◽  
Organizational Differences ◽  
Particle Reconstruction

AbstractHuman herpesvirus 6B (HHV-6B) belongs to the β-herpesvirus subfamily of the Herpesviridae. To understand capsid assembly and capsid-tegument interactions, here we report atomic structures of HHV-6B capsid and capsid-associated tegument complex (CATC) obtained by cryoEM and sub-particle reconstruction. Compared to other β-herpesviruses, HHV-6B exhibits high similarity in capsid structure but organizational differences in its CATC (pU11 tetramer). 180 “VΛ”-shaped CATCs are observed in HHV-6B, distinguishing from the 255 “Λ”-shaped dimeric CATCs observed in murine cytomegalovirus and the 310 “Δ”-shaped CATCs in human cytomegalovirus. This trend in CATC quantity correlates with the increasing genomes sizes of these β-herpesviruses. Incompatible distances revealed by the atomic structures rationalize the lack of CATC’s binding to triplexes Ta, Tc, and Tf in HHV-6B. Our results offer insights into HHV-6B capsid assembly and the roles of its tegument proteins, including not only the β-herpesvirus-specific pU11 and pU14, but also those conserved across all subfamilies of Herpesviridae.

scholarly journals Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

2008 ◽  
Vol 52 (8) ◽  
pp. 2727-2733 ◽  
Author(s):  
David I. Bernstein ◽  
Nathalie Goyette ◽  
Rhonda Cardin ◽  
Earl R. Kern ◽  
Guy Boivin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Parent Compound ◽  
Human Herpesvirus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Simplex Virus ◽  
Acid Stable

ABSTRACT Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo- and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC50], 0.02 to 0.06 μM), human cytomegalovirus (EC50, 0.02 to 0.13 μM), varicella zoster virus (EC50, <0.02 μM), Epstein-Barr virus (EC50, 14.7 μM) and human herpesvirus types 6A/B (EC50, 2.9 to 10.2 μM). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P = 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.

scholarly journals Analytical methods in herpesvirus genomics

2014 ◽  
Vol 7 (2) ◽  
pp. 109-118
Author(s):  
Jana Blaškovičová ◽  
Ján Labuda
Keyword(s):  
Analytical Methods ◽  
Genome Structure ◽  
Human Herpesvirus ◽  
B Cell Lymphoma ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
And Function ◽  
Analytical Approaches

Abstract Genomics is a branch of bioanalytical chemistry characterized as the study of the genome structure and function. Genome represents the complete set of chromosomal and extrachromosomal genes of an organism, a cell, an organelle or a virus. There are at least five from eight species of herpesviruses commonly widespread among humans, Herpes simplex virus type 1 and 2, Varicella zoster virus, Epstein-Barr virus and Cytomegalovirus. Human gammaherpesviruses can cause serious diseases including B-cell lymphoma and Kaposi’s sarcoma. Diagnostics and study of the herpesviruses is directly dependent on the development of modern analytical methods able to detect and determine the presence and evolution of herpesviral particles/ genomes. Diagnostics and genomic characterization of human herpesvirus species is based on bioanalytical methods such as polymerase chain reaction (PCR), DNA sequencing, gel electrophoresis, blotting and others. The progress in analytical approaches in the herpesvirus genomics is reviewed in this article.

scholarly journals Herpesvirus Infections of the Central Nervous System

2019 ◽  
Vol 39 (03) ◽  
pp. 369-382 ◽  
Author(s):  
Tehmina Bharucha ◽  
Catherine F. Houlihan ◽  
Judith Breuer
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Human Herpesvirus ◽  
Clinical Syndrome ◽  
Herpes Simplex Virus 1 ◽  
Varicella Zoster ◽  
Barr Virus ◽  
The Central Nervous System ◽  
Epstein Barr ◽  
Simplex Virus

AbstractThere are over 200 herpesvirus species, of which 10 affect humans. Each of these 10 herpesviruses has a unique clinical syndrome, but common to all is their ability to cause infection and pathology in the central nervous system. In this article, we discuss the epidemiology, clinical presentation, diagnostic modalities, treatment, sequelae, and availability of vaccination of each of the following herpesviruses: herpes simplex virus 1 and 2, varicella zoster virus, human cytomegalovirus, human herpesvirus 6A, 6B, and 7, Epstein–Barr virus, human herpesvirus 8, and simian herpesvirus B.

scholarly journals Inhibition of Herpesvirus Replication by 5-Substituted 4′-Thiopyrimidine Nucleosides

2009 ◽  
Vol 53 (12) ◽  
pp. 5251-5258 ◽  
Author(s):  
Mark N. Prichard ◽  
Debra C. Quenelle ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Geraldine Jefferson ◽  
...  
Keyword(s):  
Human Herpesvirus ◽  
Good Activity ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Resistant Strains ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT A series of 4′-thionucleosides were synthesized and evaluated for activities against orthopoxviruses and herpesviruses. We reported previously that one analog, 5-iodo-4′-thio-2′-deoxyuridine (4′-thioIDU), exhibits good activity both in vitro and in vivo against two orthopoxviruses. This compound also has good activity in cell culture against many of the herpesviruses. It inhibited the replication of herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus with 50% effective concentrations (EC50s) of 0.1, 0.5, and 2 μM, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC50 of 5.9 μM but did not selectively inhibit Epstein-Barr virus, human herpesvirus 6, or human herpesvirus 8. While acyclovir-resistant strains of HSV-1 and HSV-2 were comparatively resistant to 4′-thioIDU, it retained modest activity (EC50s of 4 to 12 μM) against these strains. Some ganciclovir-resistant strains of HCMV also exhibited reduced susceptibilities to the compound, which appeared to be related to the specific mutations in the DNA polymerase, consistent with the observed incorporation of the compound into viral DNA. The activity of 4′-thioIDU was also evaluated using mice infected intranasally with the MS strain of HSV-2. Although there was no decrease in final mortality rates, the mean length of survival after inoculation increased significantly (P < 0.05) for all animals receiving 4′-thioIDU. The findings from the studies presented here suggest that 4′-thioIDU is a good inhibitor of some herpesviruses, as well as orthopoxviruses, and this class of compounds warrants further study as a therapy for infections with these viruses.

scholarly journals Artemisinin-Derived Dimer Diphenyl Phosphate Is an Irreversible Inhibitor of Human Cytomegalovirus Replication

2012 ◽  
Vol 56 (7) ◽  
pp. 3508-3515 ◽  
Author(s):  
Ran He ◽  
Kyoungsook Park ◽  
Hongyi Cai ◽  
Arun Kapoor ◽  
Michael Forman ◽  
...  
Keyword(s):  
Dna Replication ◽  
Human Cytomegalovirus ◽  
Specific Activity ◽  
Tight Binding ◽  
Human Herpesvirus ◽  
Lytic Replication ◽  
Virus Yield ◽  
Irreversible Inhibitor ◽  
Barr Virus ◽  
Diphenyl Phosphate

ABSTRACTWe previously reported that among a series of artemisinin-derived monomers and dimers, dimer diphenyl phosphate (838) was the most potent inhibitor of human cytomegalovirus (CMV) replication. Our continued investigation of a prototypic artemisinin monomer (artesunate [AS]) and dimer (838) now reveals that both compounds have specific activity against CMV but do not inhibit lytic replication of human herpesvirus 1 or 2 or Epstein-Barr virus. AS and 838 inhibited CMV replication during the first 24 h of the virus replication cycle, earlier than the time of ganciclovir (GCV) activities and prior to DNA synthesis. Neither compound inhibited virus entry. Quantification of DNA replication and virus yield revealed a similar level of inhibition by GCV, but AS and 838 had a 10-fold-higher inhibition of virus yield than of DNA replication, suggesting that artemisinins could inhibit CMV through multiple steps: a predominant early inhibition and possibly an additional step following DNA replication. During the strong early CMV inhibition, the transcription of immediate-early genes was not significantly downregulated, and viral protein expression was reduced only after 48 h. AS and GCV were reversible CMV inhibitors, but the inhibition of CMV replication by 838 was irreversible. Combinations of GCV and 838 as well as GCV and AS were highly synergistic. Finally, treatment with 838, but not AS, prior to CMV infection demonstrated strong anti-CMV activity. These findings illustrate the unique activities of dimer 838, including early and irreversible CMV inhibition, possibly by tight binding to its target.

Sign in / Sign up

Export Citation Format

Share Document