Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice

Yao, Hui; Lin, Pin Hung; Shen, Fang; Perng, Guey Chuen; Tung, Yuk Ying; Hsu, Sheng Min; Chen, Shun Hua

doi:10.1128/aac.02617-13

Cited by 11 publications

(6 citation statements)

References 52 publications

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“…Reduction in viral pathology was evident in animals infected with high doses (LD 50 or LD 90 doses) and using a variety of inhibitor treatments (oral, time-release, topical, intraperitoneal). Indeed, in support of these data, Yao et al (48) reported the use of TCP to suppress HSV infection in the mouse model system. Similarly, in the rabbit eye model of herpetic keratitis, treatment of primary infection reduced the critical clinical indicators of ocular disease.…”

Section: Discussionmentioning

confidence: 82%

Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes

et al. 2014

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The high prevalence of Herpesviruses in the population and the maintenance of lifelong latent reservoirs are challenges to the control of herpetic diseases, despite the availability of antiviral pharmaceuticals that target viral DNA replication. In addition to oral and genital lesions, herpes simplex virus infections and recurrent reactivations from the latent pool can result in severe pathology including neonatal infection and mortality, blindness due to ocular keratitis, and viral-induced complications in immunosuppressed individuals. Herpesviruses, like their cellular hosts, are subject to the regulatory impacts of chromatin and chromatin modulation machinery that promotes or suppresses gene expression. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 and JMJD2s. Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and a block to infection and reactivation in vitro. Here, the concept of epigenetic suppression of viral infection is demonstrated in three animal models of herpes simplex virus infection and disease. Inhibition of LSD1 via treatment of animals with the monoamine oxidase inhibitor tranylcypromine results in suppression of viral lytic infection, subclinical shedding, and reactivation from latency in vivo. Phenotypic suppression is correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Given the expanding development of epipharmaceuticals, this approach has substantial potential for anti-herpetic treatments with distinct advantages over the present pharmaceutical options.

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Section: Discussionmentioning

confidence: 82%

Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes

et al. 2014

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“…Naproxen was reported to be incorporated into the RNA-binding groove of the nucleoprotein of influenza A virus, suggesting its potential role in antiviral research 36 . The therapeutic potential of tranylcypromine for herpes simplex virus 1 (HSV-1) infection was evaluated because of its inhibitory activity against the histone-modifying enzyme, lysine-specific demethylase 1 37 . Raloxifene, a selective oestrogen receptor modulator, was reported to inhibit Ebola virus infection 38 .…”

Section: Discussionmentioning

confidence: 99%

Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors

Chiou¹,

Hsu

Chen

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Mouse brain stems were processed and stained as described in our previous reports (40,42), using Hoechst dye for DNA and antibodies against HSV-1 (Dako), HSV-1 glycoprotein C (clone 3G9; Abcam), or mouse NeuN (clone A60; Millipore).…”

Section: Methodsmentioning

confidence: 99%

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

Huang

Yao

Wang

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484 -490, 1994, https://doi.org/10.1006/viro .1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30-to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1.IMPORTANCE Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drugresistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised patients with persistent infection. However, answers to the questions as to whether TKnegative (TK Ϫ ) HSV-1 can establish persistent infection in brains of immunocompromised hosts and whether neurons in vivo are permissive for TK Ϫ HSV-1 remain elusive. Using three genetically engineered HSV-1 TK Ϫ mutants and two strains of nude mice deficient in T cells, we found that all three HSV-1 TK Ϫ mutants can efficiently establish persistent infection in the brain stem and trigeminal ganglion and detected glycoprotein C, a true late viral antigen, in brainstem neurons. Our study provides evidence that TK Ϫ HSV-1 can persist in neural tissues and replicate in brain neurons of immunocompromised hosts.

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Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice

Cited by 11 publications

References 52 publications

Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes

Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes

Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

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