Acyclovir resistance in herpes simplex viruses: Prevalence and therapeutic alternatives

Schalkwijk, Hanna Helena; Snoeck, Robert; Andreï, Graciela

doi:10.1016/j.bcp.2022.115322

Cited by 42 publications

(21 citation statements)

References 202 publications

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“…Acyclovir resistance, which causes recurrence of symptoms and increases risk of complications, is still the main challenge in antiviral therapy. Since most antiviral drugs target viral DNA polymerases or viral thymidine kinases (TK), effective options to treat drugresistant HSV are nil [34]. Here, USGLP25 has impaired viral TK gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Nucleoside analogs, incsluding acyclovir, penciclovir, and their derivatives, are the most effective antivirals in treating HSV infections [5]. However, resistance to these antivirals, which can develop within a week of treatment, poses a great challenge to the treatment of HSV infection using these drugs [6]. Nucleoside analog’s function as HSV DNA replication inhibitors by impeding viral thymidine kinases or viral DNA polymerases, and alterations in these enzymes confer drug resistance [7].…”

Section: Introductionmentioning

confidence: 99%

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Gaudichaudione H inhibits Herpes Simplex Virus-1 replication by regulating cellular nuclear factor-κB in an interferon-γ-inde-pendent manner

Feng

Tang

et al. 2023

Preprint

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The highly prevalent herpes simplex virus type 1 (HSV-1) causes keratoconjunctivitis and encephalitis. Viral DNA polymerase-inhibiting nucleoside analogs (such as acyclovir) are standard treatment agents against HSV infections but are limited by severe drug resistance issues. Thus, new antiviral agents with novel targets are urgently needed. Earlier, we investigated the anti-cancer, anti-inflammatory, and antibacterial bioactivities of Garcinia sp. Here, we report that non-cytotoxic concentrations (< 500 nM) of Gaudichaudione H (GH, isolated from Garcinia oligantha Merr.) potently inhibits HSV-1 replication in vitro without affecting viral entry or attachment. GH inhibits the expression of the viral proteins ICP0, ICP4, and ICP27 without affecting their mRNA levels. In Vero cells, GH enhanced STAT1 and 3 phosphorylation, which occurs downstream to interferon (IFN)-γ activation during viral infections. However, pharmacological/genetic inhibition of IFN-γ failed to suppress the GH-mediated inhibition of HSV-1 replication, indicating that GH exerts antiviral effects independent of IFN. Further mechanistic studies suggest that GH inhibits HSV-1 replication, at least partially by inhibiting cellular NF-κB activation. Moreover, GH prolonged the survival rate of KOS-infected mice by 25% (n = 5). In conclusion, GH treatment inhibits HSV-1 replication both in vitro and in vivo; therefore, it can be developed as an antiviral.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gaudichaudione H inhibits Herpes Simplex Virus-1 replication by regulating cellular nuclear factor-κB in an interferon-γ-inde-pendent manner

Feng

Tang

et al. 2023

Preprint

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“…HHV is the prototype of a large family of double-stranded DNA genome viruses; human herpesvirus (HHV) types 1 and 2 establish latent infections in sensory neurons and undergo reactivation during periods of severe host immunosuppression. Prolonged therapy with acyclovir (ACV) and its analogs can lead to drug-resistant HHV strains in patients infected with the human immunodeficiency virus (HIV) [31]. Continued research in virology and pharmacology will predictably lead to the identification of new molecular targets for clinical intervention, with the objective of developing new combined treatments that will produce therapeutic synergies in the future [31,32].…”

Section: Introductionmentioning

confidence: 99%

“…Prolonged therapy with acyclovir (ACV) and its analogs can lead to drug-resistant HHV strains in patients infected with the human immunodeficiency virus (HIV) [31]. Continued research in virology and pharmacology will predictably lead to the identification of new molecular targets for clinical intervention, with the objective of developing new combined treatments that will produce therapeutic synergies in the future [31,32]. The importance of developing an integrated approach and networking in the study of natural products for advancing new therapies is essential, and The International Natural Product The combination of drugs has been historically successful for severe and chronic viral diseases such as those originating from human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections and is a developing strategy for emerging or re-emerging viral diseases, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS)-CoV, Zika, Ebola, and influenza [26].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

Betancur-Galvis,

Jimenez-Jarava,

Rivas

et al. 2023

Pharmaceuticals

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Combining antiviral drugs with different mechanisms of action can help prevent the development of resistance by attacking the infectious agent through multiple pathways. Additionally, by using faster and more economical screening methods, effective synergistic drug candidates can be rapidly identified, facilitating faster paths to clinical testing. In this work, a rapid method was standardized to identify possible synergisms from drug combinations. We analyzed the possible reduction in the antiviral effective concentration of drugs already approved by the FDA, such as ivermectin (IVM), ribavirin (RIBA), and acyclovir (ACV) against Zika virus (ZIKV), Chikungunya virus (CHIKV), and herpes virus type 2 (HHV-2). Essential oils (EOs) were also included in the study since they have been reported for more than a couple of decades to have broad-spectrum antiviral activity. We also continued studying the antiviral properties of one of our patented molecules with broad-spectrum antiviral activity, the ferruginol analog 18-(phthalimid-2-yl)ferruginol (phthFGL), which presented an IC99 of 25.6 μM for the three types of virus. In general, the combination of IVM, phthFGL, and oregano EO showed the greatest synergism potential against CHIKV, ZIKV, and HHV-2. For instance, this combination achieved reductions in the IC99 value of each component up to ~8-, ~27-, and ~12-fold for CHIKV, respectively. The ternary combination of RIBA, phthFGL, and oregano EO was slightly more efficient than the binary combination RIBA/phthFGL but much less efficient than IVM, phthFGL, and oregano EO, which indicates that IVM could contribute more to the differentiation of cell targets (for example via the inhibition of the host heterodimeric importin IMP α/β1 complex) than ribavirin. Statistical analysis showed significant differences among the combination groups tested, especially in the HHV-2 and CHIKV models, with p = 0.0098. Additionally, phthFGL showed a good pharmacokinetic profile that should encourage future optimization studies.

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Management of Refractory/Resistant Herpes Simplex Virus Infections in Haematopoietic Stem Cell Transplantation Recipients: A Literature Review

Sallée,

Boutolleau

2024

Reviews in Medical Virology

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Herpes simplex virus (HSV) infections in allogeneic haematopoietic stem cell transplantation (HSCT) recipients pose significant challenges, with higher incidence, severity, and risk of emergence of resistance to antivirals due to impaired T‐cell mediated immunity. This literature review focuses on acyclovir‐refractory/resistant HSV infections in HSCT recipients. The review addresses the efficacy of antiviral prophylaxis, the incidence of acyclovir‐refractory/resistant HSV infections, and the identification of risk factors and potential prognostic impact associated with those infections. Additionally, alternative therapeutic options are discussed. While acyclovir prophylaxis demonstrates a significant benefit in reducing HSV infections in HSCT recipients and, in some cases, overall mortality, concerns arise about the emergence of drug‐resistant HSV strains. Our systematic review reports a median incidence of acyclovir‐resistant HSV infections of 16.1%, with an increasing trend in recent years. Despite limitations in available studies, potential risk factors of emergence of HSV resistance to acyclovir include human leucocyte antigen (HLA) mismatches, myeloid neoplasms and acute leukaemias, and graft‐versus‐host disease (GVHD). Limited evidences suggest a potentially poorer prognosis for allogeneic HSCT recipients with acyclovir‐refractory/resistant HSV infection. Alternative therapeutic approaches, such as foscarnet, cidofovir, topical cidofovir, optimised acyclovir dosing, and helicase‐primase inhibitors offer promising options but require further investigations. Overall, larger studies are needed to refine preventive and therapeutic strategies for acyclovir‐refractory/resistant HSV infections in allogeneic HSCT recipients and to identify those at higher risk.

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Acyclovir resistance in herpes simplex viruses: Prevalence and therapeutic alternatives

Cited by 42 publications

References 202 publications

Gaudichaudione H inhibits Herpes Simplex Virus-1 replication by regulating cellular nuclear factor-κB in an interferon-γ-inde-pendent manner

Gaudichaudione H inhibits Herpes Simplex Virus-1 replication by regulating cellular nuclear factor-κB in an interferon-γ-inde-pendent manner

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

Management of Refractory/Resistant Herpes Simplex Virus Infections in Haematopoietic Stem Cell Transplantation Recipients: A Literature Review

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