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19 pages, 3863 KiB

Open AccessArticle

Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice

by Maimoona S. Bhutta, Oren Shechter, Elisa S. Gallo, Stephen D. Martin, Esther Jones, Gustavo F. Doncel and Ronen Borenstein

Viruses 2021, 13(1), 86; https://doi.org/10.3390/v13010086 - 9 Jan 2021

Cited by 18 | Viewed by 4275

Abstract

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral [...] Read more.

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACV^R-HSV) have been isolated from immunocompromised patients. Thus, ACV^R-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA’s antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACV^R-HSV-1 strain 17+ in vitro and in vivo. Since GA’s mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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10 pages, 619 KiB

Open AccessArticle

Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity

by Kiira Kalke, Jenni Lehtinen, Jelena Gnjatovic, Liisa M. Lund, Marie C. Nyman, Henrik Paavilainen, Julius Orpana, Tuomas Lasanen, Fanny Frejborg, Alesia A. Levanova, Tytti Vuorinen, Minna M. Poranen and Veijo Hukkanen

Viruses 2020, 12(12), 1434; https://doi.org/10.3390/v12121434 - 13 Dec 2020

Cited by 14 | Viewed by 3546

Abstract

Acyclovir is the drug of choice for the treatment of herpes simplex virus (HSV) infections. Acyclovir-resistant HSV strains may emerge, especially during long-term drug use, and subsequently cause difficult-to-treat exacerbations. Previously, we set up a novel treatment approach, based on enzymatically synthesized pools [...] Read more.

Acyclovir is the drug of choice for the treatment of herpes simplex virus (HSV) infections. Acyclovir-resistant HSV strains may emerge, especially during long-term drug use, and subsequently cause difficult-to-treat exacerbations. Previously, we set up a novel treatment approach, based on enzymatically synthesized pools of siRNAs, or siRNA swarms. These swarms can cover kilobases-long target sequences, reducing the likelihood of resistance to treatment. Swarms targeting the UL29 essential gene of HSV-1 have demonstrated high efficacy against HSV-1 in vitro and in vivo. Here, we assessed the antiviral potential of a UL29 siRNA swarm against circulating strains of HSV-1, in comparison with acyclovir. All circulating strains were sensitive to both antivirals, with the half-maximal inhibitory concentrations (IC₅₀) in the range of 350–1911 nM for acyclovir and 0.5–3 nM for the UL29 siRNA swarm. Additionally, we showed that an acyclovir-resistant HSV-1, devoid of thymidine kinase, is highly sensitive to UL29 siRNA treatment (IC₅₀ 1.0 nM; I_max 97%). Moreover, the detected minor variations in the RNAi target of the HSV strains had no effect on the potency or efficacy of UL29 siRNA swarm treatment. Our findings support the development of siRNA swarms for the treatment of HSV-1 infections, in order to circumvent any potential acyclovir resistance. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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Review

Jump to: Research

28 pages, 2421 KiB

Open AccessReview

The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection

by Thomas R. O’Neil, Kevin Hu, Naomi R. Truong, Sana Arshad, Barbara L. Shacklett, Anthony L. Cunningham and Najla Nasr

Viruses 2021, 13(3), 359; https://doi.org/10.3390/v13030359 - 25 Feb 2021

Cited by 12 | Viewed by 4872

Abstract

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8⁺ TRM, there has recently been increased interest in defining the phenotype and the role of CD4⁺ TRM in diseases. Circulating CD4⁺ T [...] Read more.

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8⁺ TRM, there has recently been increased interest in defining the phenotype and the role of CD4⁺ TRM in diseases. Circulating CD4⁺ T cells seed CD4⁺ TRM, but there also appears to be an equilibrium between CD4⁺ TRM and blood CD4⁺ T cells. CD4⁺ TRM are more mobile than CD8⁺ TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8⁺ TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4⁺ and CD8⁺ TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8⁺ T cells. The exact role of the CD4⁺/CD8⁺ TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4⁺ TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4⁺ TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4⁺ TRM and their induction by vaccines may help control sexual transmission by both viruses. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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12 pages, 530 KiB

Open AccessReview

Development of Genome Editing Approaches against Herpes Simplex Virus Infections

by Isadora Zhang, Zoe Hsiao and Fenyong Liu

Viruses 2021, 13(2), 338; https://doi.org/10.3390/v13020338 - 22 Feb 2021

Cited by 9 | Viewed by 4464

Abstract

Herpes simplex virus 1 (HSV-1) is a herpesvirus that may cause cold sores or keratitis in healthy or immunocompetent individuals, but can lead to severe and potentially life-threatening complications in immune-immature individuals, such as neonates or immune-compromised patients. Like all other herpesviruses, HSV-1 [...] Read more.

Herpes simplex virus 1 (HSV-1) is a herpesvirus that may cause cold sores or keratitis in healthy or immunocompetent individuals, but can lead to severe and potentially life-threatening complications in immune-immature individuals, such as neonates or immune-compromised patients. Like all other herpesviruses, HSV-1 can engage in lytic infection as well as establish latent infection. Current anti-HSV-1 therapies effectively block viral replication and infection. However, they have little effect on viral latency and cannot completely eliminate viral infection. These issues, along with the emergence of drug-resistant viral strains, pose a need to develop new compounds and novel strategies for the treatment of HSV-1 infection. Genome editing methods represent a promising approach against viral infection by modifying or destroying the genetic material of human viruses. These editing methods include homing endonucleases (HE) and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR associated protein (Cas) RNA-guided nuclease system. Recent studies have showed that both HE and CRISPR/Cas systems are effective in inhibiting HSV-1 infection in cultured cells in vitro and in mice in vivo. This review, which focuses on recently published progress, suggests that genome editing approaches could be used for eliminating HSV-1 latent and lytic infection and for treating HSV-1 associated diseases. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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19 pages, 1053 KiB

Open AccessReview

The Role of ND10 Nuclear Bodies in Herpesvirus Infection: A Frenemy for the Virus?

by Behdokht Jan Fada, Eleazar Reward and Haidong Gu

Viruses 2021, 13(2), 239; https://doi.org/10.3390/v13020239 - 3 Feb 2021

Cited by 6 | Viewed by 3632

Abstract

Nuclear domains 10 (ND10), a.k.a. promyelocytic leukemia nuclear bodies (PML-NBs), are membraneless subnuclear domains that are highly dynamic in their protein composition in response to cellular cues. They are known to be involved in many key cellular processes including DNA damage response, transcription [...] Read more.

Nuclear domains 10 (ND10), a.k.a. promyelocytic leukemia nuclear bodies (PML-NBs), are membraneless subnuclear domains that are highly dynamic in their protein composition in response to cellular cues. They are known to be involved in many key cellular processes including DNA damage response, transcription regulation, apoptosis, oncogenesis, and antiviral defenses. The diversity and dynamics of ND10 residents enable them to play seemingly opposite roles under different physiological conditions. Although the molecular mechanisms are not completely clear, the pro- and anti-cancer effects of ND10 have been well established in tumorigenesis. However, in herpesvirus research, until the recently emerged evidence of pro-viral contributions, ND10 nuclear bodies have been generally recognized as part of the intrinsic antiviral defenses that converge to the incoming viral DNA to inhibit the viral gene expression. In this review, we evaluate the newly discovered pro-infection influences of ND10 in various human herpesviruses and analyze their molecular foundation along with the traditional antiviral functions of ND10. We hope to shed light on the explicit role of ND10 in both the lytic and latent cycles of herpesvirus infection, which is imperative to the delineation of herpes pathogenesis and the development of prophylactic/therapeutic treatments for herpetic diseases. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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75 pages, 5071 KiB

Open AccessReview

“Non-Essential” Proteins of HSV-1 with Essential Roles In Vivo: A Comprehensive Review

by Christos Dogrammatzis, Hope Waisner and Maria Kalamvoki

Viruses 2021, 13(1), 17; https://doi.org/10.3390/v13010017 - 23 Dec 2020

Cited by 23 | Viewed by 9649

Abstract

Viruses encode for structural proteins that participate in virion formation and include capsid and envelope proteins. In addition, viruses encode for an array of non-structural accessory proteins important for replication, spread, and immune evasion in the host and are often linked to virus [...] Read more.

Viruses encode for structural proteins that participate in virion formation and include capsid and envelope proteins. In addition, viruses encode for an array of non-structural accessory proteins important for replication, spread, and immune evasion in the host and are often linked to virus pathogenesis. Most virus accessory proteins are non-essential for growth in cell culture because of the simplicity of the infection barriers or because they have roles only during a state of the infection that does not exist in cell cultures (i.e., tissue-specific functions), or finally because host factors in cell culture can complement their absence. For these reasons, the study of most nonessential viral factors is more complex and requires development of suitable cell culture systems and in vivo models. Approximately half of the proteins encoded by the herpes simplex virus 1 (HSV-1) genome have been classified as non-essential. These proteins have essential roles in vivo in counteracting antiviral responses, facilitating the spread of the virus from the sites of initial infection to the peripheral nervous system, where it establishes lifelong reservoirs, virus pathogenesis, and other regulatory roles during infection. Understanding the functions of the non-essential proteins of herpesviruses is important to understand mechanisms of viral pathogenesis but also to harness properties of these viruses for therapeutic purposes. Here, we have provided a comprehensive summary of the functions of HSV-1 non-essential proteins. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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9 pages, 1832 KiB

Open AccessReview

Valproic Acid and Its Amidic Derivatives as New Antivirals against Alphaherpesviruses

by Sabina Andreu, Inés Ripa, Raquel Bello-Morales and José Antonio López-Guerrero

Viruses 2020, 12(12), 1356; https://doi.org/10.3390/v12121356 - 26 Nov 2020

Cited by 17 | Viewed by 2934

Abstract

Herpes simplex viruses (HSVs) are neurotropic viruses with broad host range whose infections cause considerable health problems in both animals and humans. In fact, 67% of the global population under the age of 50 are infected with HSV-1 and 13% have clinically recurrent [...] Read more.

Herpes simplex viruses (HSVs) are neurotropic viruses with broad host range whose infections cause considerable health problems in both animals and humans. In fact, 67% of the global population under the age of 50 are infected with HSV-1 and 13% have clinically recurrent HSV-2 infections. The most prescribed antiherpetics are nucleoside analogues such as acyclovir, but the emergence of mutants resistant to these drugs and the lack of available vaccines against human HSVs has led to an imminent need for new antivirals. Valproic acid (VPA) is a branched short-chain fatty acid clinically used as a broad-spectrum antiepileptic drug in the treatment of neurological disorders, which has shown promising antiviral activity against some herpesviruses. Moreover, its amidic derivatives valpromide and valnoctamide also share this antiherpetic activity. This review summarizes the current research on the use of VPA and its amidic derivatives as alternatives to traditional antiherpetics in the fight against HSV infections. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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16 pages, 1462 KiB

Open AccessReview

Evasion of the Cell-Mediated Immune Response by Alphaherpesviruses

by Naoto Koyanagi and Yasushi Kawaguchi

Viruses 2020, 12(12), 1354; https://doi.org/10.3390/v12121354 - 26 Nov 2020

Cited by 17 | Viewed by 3441

Abstract

Alphaherpesviruses cause various diseases and establish life-long latent infections in humans and animals. These viruses encode multiple viral proteins and miRNAs to evade the host immune response, including both innate and adaptive immunity. Alphaherpesviruses evolved highly advanced immune evasion strategies to be able [...] Read more.

Alphaherpesviruses cause various diseases and establish life-long latent infections in humans and animals. These viruses encode multiple viral proteins and miRNAs to evade the host immune response, including both innate and adaptive immunity. Alphaherpesviruses evolved highly advanced immune evasion strategies to be able to replicate efficiently in vivo and produce latent infections with recurrent outbreaks. This review describes the immune evasion strategies of alphaherpesviruses, especially against cytotoxic host immune responses. Considering these strategies, it is important to evaluate whether the immune evasion mechanisms in cell cultures are applicable to viral propagation and pathogenicity in vivo. This review focuses on cytotoxic T lymphocytes (CTLs), natural killer cells (NK cells), and natural killer T cells (NKT cells), which are representative immune cells that directly damage virus-infected cells. Since these immune cells recognize the ligands expressed on their target cells via specific activating and/or inhibitory receptors, alphaherpesviruses make several ligands that may be targets for immune evasion. In addition, alphaherpesviruses suppress the infiltration of CTLs by downregulating the expression of chemokines at infection sites in vivo. Elucidation of the alphaherpesvirus immune evasion mechanisms is essential for the development of new antiviral therapies and vaccines. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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13 pages, 3821 KiB

Open AccessReview

Twelve Children with Varicella Vaccine Meningitis: Neuropathogenesis of Reactivated Live Attenuated Varicella Vaccine Virus

by Ethan H. Heusel and Charles Grose

Viruses 2020, 12(10), 1078; https://doi.org/10.3390/v12101078 - 25 Sep 2020

Cited by 22 | Viewed by 4473

Abstract

Varicella vaccine is a live attenuated varicella-zoster virus (VZV). Like its parental strain called VZV pOka, the vaccine virus vOka retains some neurotropic properties. To better understand vOka neuropathogenesis, we reassessed 12 published cases of vOka meningitis that occurred in once-immunized and twice-immunized [...] Read more.

Varicella vaccine is a live attenuated varicella-zoster virus (VZV). Like its parental strain called VZV pOka, the vaccine virus vOka retains some neurotropic properties. To better understand vOka neuropathogenesis, we reassessed 12 published cases of vOka meningitis that occurred in once-immunized and twice-immunized children, all of whom had bouts of herpes zoster preceding the central nervous system infection. Eight of the 12 meningitis cases occurred in children who had received only one immunization. There was no pattern to the time interval between varicella vaccination and the onset of herpes zoster with meningitis. Four of the meningitis cases occurred in children who had received two immunizations. Since all four children were 14 years old when meningitis was diagnosed, there was a strong pattern to the interval between the first vaccination at age 1 year and onset of meningitis, namely, 13 years. Knowledge of pathogenesis requires knowledge of the location of herpes zoster; the majority of dermatomal rashes occurred at sites of primary immunization on the arm or thigh, while herpes zoster ophthalmicus was uncommon. Based on this literature review, currently there is no consensus as to the cause of varicella vaccine meningitis in twice-immunized children. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Antiviral Targets of Alphaherpesviruses)

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