A nuclear receptor involved in cholesterol metabolism regulates herpesvirus latency and reactivation

Abstract

Abstract Herpesviruses are a component of our virome, and infect virtually everyone. They establish chronic latent infection that is punctuated with periods of viral reactivation. Reactivation is thought to drive herpesvirus pathologies, including lymphomas and tumors. However, the signals that promote herpesvirus reactivation are poorly understood. We previously showed that parasite co-infection could induce herpesvirus reactivation through the induction of the cytokines IL-4 and IL-13, and activation of Stat6. Stat6 directly binds to a viral promoter and induces virus reactivation, suggesting that the virus has evolved to sense immune signals from the host to modulate reactivation. We sought to identify other factors that induce herpesvirus reactivation through the modulation of inflammation. We found that peroxisome proliferator-activated receptor (PPAR)-a, a ligand-activated nuclear receptor, is upregulated during g-herpesvirus infection. PPAR-a is activated by endogenous fatty acids to regulate cholesterol metabolism. PPARs also regulate inflammation, although these functions are less well understood. We found that agonist activation of PPAR-a induces herpesvirus reactivation. PPAR-a activation dampens type I interferon signaling, by inhibiting genes that modulate the DNA sensing pathway. These data suggest that in addition to evolving cytokine-sensitive promoters, herpesviruses induce cellular machinery that sense fatty acids as a means of regulating viral reactivation.