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Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection.

ABSTRACT: Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent within the human population and are characterized by lifelong infections and sporadic recurrences due to latent neuron infection. Upon reactivations, HSVs may manifest either, symptomatically or asymptomatically and be shed onto others through mucosae body fluids. Although, HSVs can produce severe disease in humans, such as life-threatening encephalitis and blindness, the most common symptoms are skin and mucosal lesions in the oro-facial and the genital areas. Nucleoside analogs with antiviral activity can prevent severe HSV infection, yet they are not very effective for treating skin manifestations produced by these viruses, as they only reduce in a few days at most the duration of lesions. Additionally, HSV variants that are resistant to these antivirals may arise, especially in immunosuppressed individuals. Thus, new antivirals that can reduce the severity and duration of these cutaneous manifestations would certainly be welcome. Here, we review currently available anti-herpetic therapies, novel molecules being assessed in clinical trials and new botanical compounds reported in the last 20 years with antiviral activities against HSVs that might represent future treatments against these viruses.

SUBMITTER: Alvarez DM

PROVIDER: S-EPMC7026011 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection.

Álvarez Diana M DM Castillo Estefanía E Duarte Luisa F LF Arriagada José J Corrales Nicolás N Farías Mónica A MA Henríquez Adolfo A Agurto-Muñoz Cristian C González Pablo A PA

Frontiers in microbiology 20200211

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent within the human population and are characterized by lifelong infections and sporadic recurrences due to latent neuron infection. Upon reactivations, HSVs may manifest either, symptomatically or asymptomatically and be shed onto others through mucosae body fluids. Although, HSVs can produce severe disease in humans, such as life-threatening encephalitis and blindness, the most common symptoms are skin and mucosal lesio ...[more]

PMID: 32117158

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Project description:Understanding the molecular mechanisms of herpes simplex virus 1 (HSV-1) latent infection and reactivation in neurons requires the use of in vitro model systems. Establishing a quiescent infection in cultured neurons is problematic, as any infectious virus released can superinfect the cultures. Previous studies have used the viral DNA replication inhibitor acyclovir to prevent superinfection and promote latency establishment. Data from these previous models have shown that reactivation is biphasic, with an initial phase I expression of all classes of lytic genes, which occurs independently of histone demethylase activity and viral DNA replication but is dependent on the cell stress protein DLK. Here, we describe a new model system using HSV-1 Stayput-GFP, a reporter virus that is defective for cell-to-cell spread and establishes latent infections without the need for acyclovir. The establishment of a latent state requires a longer time frame than previous models using DNA replication inhibitors. This results in a decreased ability of the virus to reactivate using established inducers, and as such, a combination of reactivation triggers is required. Using this system, we demonstrate that biphasic reactivation occurs even when latency is established in the absence of acyclovir. Importantly, phase I lytic gene expression still occurs in a histone demethylase and viral DNA replication-independent manner and requires DLK activity. These data demonstrate that the two waves of viral gene expression following HSV-1 reactivation are independent of secondary infection and not unique to systems that require acyclovir to promote latency establishment. IMPORTANCE Herpes simplex virus-1 (HSV-1) enters a latent infection in neurons and periodically reactivates. Reactivation manifests as a variety of clinical symptoms. Studying latency and reactivation in vitro is invaluable, allowing the molecular mechanisms behind both processes to be targeted by therapeutics that reduce the clinical consequences. Here, we describe a novel in vitro model system using a cell-to-cell spread-defective HSV-1, known as Stayput-GFP, which allows for the study of latency and reactivation at the single neuron level. We anticipate this new model system will be an incredibly valuable tool for studying the establishment and reactivation of HSV-1 latent infection in vitro. Using this model, we find that initial reactivation events are dependent on cellular stress kinase DLK but independent of histone demethylase activity and viral DNA replication. Our data therefore further validate the essential role of DLK in mediating a wave of lytic gene expression unique to reactivation.

Dataset Information

Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection.

Publications

Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection.

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