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Viruses
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Mechanisms of Herpesvirus Resistance
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Mechanisms of Herpesvirus Resistance

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 2616

Special Issue Editor

Prof. Dr. Graciela Andrei

E-Mail Website
Guest Editor
Rega Institute, Department of Microbiology, Immunomogy & Transplantation, KU Leuven, Leuven, Belgium
Interests: virology; DNA viruses; antivirals; drug resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Herpesviruses are common human pathogens, generally causing mild to asymptomatic infections in immunocompetent hosts. However, human herpesvirus infections are more serious when the host has a weak immune system, causing significant morbidity and mortality among different populations of immunocompromised hosts. An important feature of all herpesviruses is their ability to establish lifelong latent infections after a primary infection, remaining dormant. Reactivation of herpesviruses often occurs when the immune system is impaired, causing life-threatening persistent infections that require prolonged treatment. Such prolonged treatment coupled with an impaired immune system provides the perfect selective landscape for the emergence and selection of drug-resistant mutants. Herpesviruses bearing mutations in genes associated with drug resistance can cause severe infections and extreme discomfort and eventually death among immunocompromised patients. Drug resistance is also increasingly being recognized in immunocompetent individuals suffering from herpetic keratitis.

This Special Issue of Viruses will focus on the latest advances in understanding the mechanism of herpesvirus drug resistance for the different classes of anti-herpesvirus drugs, encompassing in vitro, in vivo, and clinical research. We will also delve into the diagnosis of herpesvirus drug resistance as well as the development of new drugs and strategies to manage drug-resistant herpesvirus infections in the clinic. We invite you to share your most insightful primary research work, reviews, and hypotheses on these important topics.

Prof. Dr. Graciela Andrei
Guest Editor

Manuscript Submission Information

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Keywords

  • human herpesviruses
  • cytomegalovirus
  • drug resistance
  • antiviral agents
  • immunocompromised host
  • novel anti-herpesvirus therapies
  • DNA polymerase
  • terminase

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Published Papers (3 papers)

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Research

16 pages, 871 KiB  
Article
Primary HSV-2 Infection in an Immunocompromised Patient Reveals High Diversity of Drug-Resistance Mutations in the Viral DNA Polymerase
by Hanna Helena Schalkwijk, Sarah Gillemot, Emilie Frobert, Florence Morfin, Sophie Ducastelle, Anne Conrad, Pierre Fiten, Ghislain Opdenakker, Robert Snoeck and Graciela Andrei
Viruses 2025, 17(7), 962; https://doi.org/10.3390/v17070962 - 9 Jul 2025
Viewed by 202
Abstract
Herpes simplex virus 2 (HSV-2) remains a significant cause of morbidity and mortality in immunocompromised individuals, despite the availability of effective antivirals. Infections caused by drug-resistant isolates are an emerging concern among these patients. Understanding evolutionary aspects of HSV-2 resistance is crucial for [...] Read more.
Herpes simplex virus 2 (HSV-2) remains a significant cause of morbidity and mortality in immunocompromised individuals, despite the availability of effective antivirals. Infections caused by drug-resistant isolates are an emerging concern among these patients. Understanding evolutionary aspects of HSV-2 resistance is crucial for designing improved therapeutic strategies. Here, we characterized 11 HSV-2 isolates recovered from various body sites of a single immunocompromised patient suffering from a primary HSV-2 infection unresponsive to acyclovir and foscarnet. The isolates were analyzed phenotypically and genotypically (Sanger sequencing of viral thymidine kinase and DNA polymerase genes). Viral clone isolations, deep sequencing, viral growth kinetics, and dual infection competition assays were performed retrospectively to assess viral heterogeneity and fitness. Sanger sequencing identified mixed populations of DNA polymerase mutant variants. Viral clones were plaque-purified and genotyped, revealing 17 DNA polymerase mutations (K533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789T/K, Y823C, V842M, R847C, F923L, T934A, and R964H) associated with acyclovir and foscarnet resistance. Deep-sequencing of the DNA polymerase detected drug-resistant variants ranging between 1 and 95%, although the first two isolates had a wild-type DNA polymerase. Some mutants showed reduced fitness, evidenced by (i) the frequency of variants identified by deep-sequencing not correlating with the proportion of mutants found by plaque-purification, (ii) loss of the variants upon passaging in cell culture, or (iii) reduced frequencies in competition assays. This study reveals the rapid evolution of heterogeneous drug-resistant HSV-2 populations under antiviral therapy, highlighting the need for alternative treatment options and resistance surveillance, especially in severe infections. Full article
(This article belongs to the Special Issue Mechanisms of Herpesvirus Resistance)
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27 pages, 9428 KiB  
Article
In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2
by Jocelyne Piret and Guy Boivin
Viruses 2025, 17(7), 941; https://doi.org/10.3390/v17070941 - 2 Jul 2025
Viewed by 333
Abstract
Infections with cytomegalovirus (CMV) can result in increased morbidity and mortality in immunocompromised patients. The pUL97 kinase is a critical enzyme in the regulation of CMV replication. Although it does not phosphorylate deoxynucleosides, this enzyme is involved in the first phosphorylation step of [...] Read more.
Infections with cytomegalovirus (CMV) can result in increased morbidity and mortality in immunocompromised patients. The pUL97 kinase is a critical enzyme in the regulation of CMV replication. Although it does not phosphorylate deoxynucleosides, this enzyme is involved in the first phosphorylation step of ganciclovir (GCV), a viral DNA polymerase inhibitor. In contrast, maribavir (MBV) is a specific inhibitor of pUL97 kinase activity. In this paper, we analyzed the already-reported amino acid changes, conferring resistance to MBV and cross-resistance to GCV, in the pUL97 protein structure, predicted with AlphaFold2. Docking experiments suggest that MBV is a dual-site inhibitor, targeting ATP binding and substrate phosphorylation. Substitutions that confer resistance to MBV only may directly or indirectly alter the shape of the cavity in the vicinity of the invariant K355 in the putative ATP binding site, without affecting the viral growth. The most frequently encountered T409M substitution may correspond to a gatekeeper mutation. Substitutions that induce cross-resistance to MBV and GCV may directly or indirectly affect the environment of D456 and N461 residues in the catalytic loop, with reduced viral replicative capacity. These results have implications for the clinical use of MBV as well as for the design of novel pUL97 kinase inhibitors. Full article
(This article belongs to the Special Issue Mechanisms of Herpesvirus Resistance)
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11 pages, 1311 KiB  
Article
A Mutation in the Herpes Simplex Virus Type 1 (HSV-1) UL29 Gene is Associated with Anti-Herpesvirus Drugs’ Susceptibility
by Souichi Yamada, Shizuko Harada, Hikaru Fujii, Hitomi Kinoshita, Phu Hoang Anh Nguyen, Miho Shibamura, Tomoki Yoshikawa, Madoka Kawahara, Hideki Ebihara, Masayuki Saijo and Shuetsu Fukushi
Viruses 2024, 16(12), 1813; https://doi.org/10.3390/v16121813 - 21 Nov 2024
Viewed by 1377
Abstract
Herpes simplex virus type 1 (HSV-1) acyclovir (ACV) resistance is acquired by mutations in the viral thymidine kinase (TK) or DNA polymerase (DNApol) genes. We previously obtained an ACV-resistant clone (HSV-1_VZV_TK_clone α) by sequential passages of HSV-1_VZV-TK, a recombinant virus which lacked its [...] Read more.
Herpes simplex virus type 1 (HSV-1) acyclovir (ACV) resistance is acquired by mutations in the viral thymidine kinase (TK) or DNA polymerase (DNApol) genes. We previously obtained an ACV-resistant clone (HSV-1_VZV_TK_clone α) by sequential passages of HSV-1_VZV-TK, a recombinant virus which lacked its endogenous TK activity and instead expressed the varicella-zoster virus (VZV) TK ectopically. HSV-1_VZV_TK_clone α had been generated using an HSV-1_BAC in the presence of increasing concentrations of ACV. The ACV-resistant clone bore normal TK and DNApol genes. Here, we deployed next-generation full-genome sequencing of HSV-1_VZV_TK_clone α and identified a single nucleotide substitution, resulting in a P597L missense mutation in the UL29 gene product, the ICP8 protein. Recombinant HSV-1 encoding a P597L ICP8 protein was generated, and its properties and ability to confer drug resistance were analyzed. No difference in virus growth and UL29 expression was observed between the mutant recombinant, the wild type, and a revertant mutant viral strain, and susceptibility tests of these strains to ACV and other drugs using Vero, HEL, and ARPE19 cells identified that the recombinant UL29 mutant virus was resistant only to ACV. These results indicate that ICP8 may be involved in the anti-herpesvirus drugs’ mechanism of action on HSV-1. Full article
(This article belongs to the Special Issue Mechanisms of Herpesvirus Resistance)
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