Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation From Latency by Preventing Virus-induced Systemic Inflammation. Autophagy and Gammaherpesvirus

Host genes regulating chronic virus infection-associated systemic inflammation are incompletely understood. Chronic murine γ-herpesvirus 68 (MHV68) infection is associated with latency in macrophages. Interferon-γ (IFN-γ) inhibits reactivation from latency. Here we show that Lysozyme-M-cre (LysMcre) expression-driven deletion of the autophagy-related (Atg) genes Fip200, beclin 1, Atg14, Atg16L1, Atg7, Atg3, and Atg5 inhibited MHV68 reactivation from latency in macrophages. Detailed studies of Atg5-deficiency revealed that the reactivation defect occurred in macrophages but not in B cells and was not explained by alterations in productive viral replication or the establishment of latency. Chronic MHV68 infection triggered increased systemic inflammation, increased T cell production of IFN-γ and an IFN-γ-induced transcriptional signature in macrophages in Atg5-deficient mice. The Atg5-related reactivation defect was partially reversed by neutralization of IFN-γ. Thus, Atg genes are responsible for dampening virus-induced systemic inflammation, and this effect is required for efficient MHV68 reactivation from latency.