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Herpesviruses are ubiquitous human pathogens that tightly regulate many cellular pathways including the unfolded protein response to endoplasmic reticulum (ER) stress. Pharmacological modulation of this pathway results in the inhibition of viral replication. In this study, we tested 4-phenylbutyrate (PBA), a chemical chaperone-based potent alleviator of ER stress, for its effects on herpes simplex virus (HSV) type 1 infection. Through in vitro studies, we observed that application of PBA to HSV-infected cells results in the down-regulation of a proviral, ER-localized host protein CREB3 and a resultant inhibition of viral protein synthesis. PBA treatment caused viral inhibition in cultured human corneas and human skin grafts as well as murine models of ocular and genital HSV infection. Thus, we propose that this drug can provide an alternative to current antivirals to treat both ocular HSV-1 and genital HSV-2 infections and may be a strong candidate for human trials.

Standalone or combinatorial phenylbutyrate therapy shows excellent antiviral activity and mimics CREB3 silencing