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

Hill JM, Quenelle DC, Cardin RD, Vogel JL, Clement C, Bravo FJ, Foster TP, Bosch-Marce M, Raja P, Lee JS, Bernstein DI, Krause PR, Knipe DM, Kristie TM.

Sci Transl Med. (2014) 6:265ra169.

Speaker: Chi-Ting Hsieh (謝其庭)                                 Time: 15:10~16:00, Mar. 4, 2015

Commentator: Dr. Shun-hua Chen (陳舜華老師)        Place: Room 601

Abstract:

       Herpes simplex virus (HSV) establishes lifelong latent infection among over 80% of human population worldwide and causes HSV-associated diseases, including encephalitis and herpetic keratitis. The therapeutic strategy of current anti-HSV drugs such as acyclovir is based on inhibition of viral DNA synthesis. Those drugs, however, fail to completely block virus shedding, reactivation and virus-induced inflammation; moreover they drive development of drug-resistant viruses. Therefore, an alternative approach to treat herpetic diseases is under consideration. Previous studies indicate that cellular lysine-specific demethylase 1A (LSD1) is required for resolving chromatin structure and thus initiating viral gene transcription. Inhibition of LSD1 by tranylcypromine (TCP) can block HSV replication and reactivation in vitro [1], but it remains unclear whether TCP is also an effective anti-HSV drug in vivo. In this study, the authors used three animal models, representing different HSV infection states in vivo, to test the efficacy of TCP for HSV-related diseases. A mouse model was used to quantify mortality rates and local viral loads during ocular or intranasal HSV-1 infection. The rabbit model was used to examine the clinical symptoms of HSV-1 keratitis and the viral shedding from spontaneous reactivation. The guinea pig genital model was used to monitor clinical lesion recurrence resulting from HSV-2 reactivation. Collectively, TCP significantly decreased mortality, viral loads, keratitis scores, viral shedding, viral reactivation and disease recurrence in these animal models, with no obvious toxicity. In addition, combined treatment of acyclovir with TCP enhanced the therapeutic efficacy compared with that using either compound alone. Since inhibition of LSD1 can reduce lytic infection, subclinical shedding and reactivation of HSV, modulation of the epigenetic state of herpesvirus genomes should be a promising strategy to control herpetic diseases.

Reference:

1.    Liang, Y., et al., Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nat Med, 2009. 15(11): p. 1312-7.