WY14643 Increases Herpesvirus Replication and Inhibits IFNβ Production Independently of PPARα Expression

Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPARα with clinically relevant ligands could impact gammaherpesvirus infection using murine gammaherpesvirus-68 (MHV68, MuHV-4). We found that PPAR agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARα. We found that WY14643 suppressed production of type I interferon after MHV68 infection in vitro and in vivo. Taken together, our data indicate that caution should be employed when using PPARα agonists in immuno-metabolic studies, as they can have off-target effects on viral replication through the inhibition of type I interferon production. IMPORTANCE PPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field for two reasons. First, it shows a role for PPARα agonists in altering virus replication. Second, it shows that PPARα agonists can affect virus replication in a manner independent of their predicted target. This knowledge is valuable for anyone seeking to use PPARα agonists as a research tool.