LXR Alpha Restricts Gammaherpesvirus Reactivation from Latently Infected Peritoneal Cells

Abstract

Gammaherpesviruses are ubiquitous viruses that establish lifelong infections. Importantly, these viruses are associated with numerous cancers and lymphoproliferative diseases. While risk factors for developing gammaherpesvirus-driven cancers are poorly understood, it is clear that elevated viral reactivation from latency often precedes oncogenesis. Here, we demonstrate that the liver X receptor alpha isoform (LXRα) restricts gammaherpesvirus reactivation in an anatomic-site-specific manner. We have previously demonstrated that deficiency of both LXR isoforms (α and β) leads to an increase in fatty acid and cholesterol synthesis in primary macrophage cultures, with a corresponding increase in gammaherpesvirus replication. Interestingly, expression of fatty acid synthesis genes was not derepressed in LXRα-deficient hosts, indicating that the antiviral effects of LXRα are independent of lipogenesis. Additionally, the critical host defenses against gammaherpesvirus reactivation, virus-specific CD8+ T cells and interferon (IFN) signaling, remained intact in the absence of LXRα. Remarkably, using a murine gammaherpesvirus 68 (MHV68) reporter virus, we discovered that LXRα expression dictates the cellular tropism of MHV68 in the peritoneal cavity. Specifically, LXRα−/− mice exhibit reduced latency within the peritoneal B cell compartment and elevated latency within F4/80+ cells. Thus, LXRα restricts gammaherpesvirus reactivation through a novel mechanism that is independent of the known CD8+ T cell-based antiviral responses or changes in lipid synthesis and likely involves changes in the tropism of MHV68 in the peritoneal cavity. IMPORTANCE Liver X receptors (LXRs) are nuclear receptors that mediate cholesterol and fatty acid homeostasis. Importantly, as ligand-activated transcription factors, LXRs represent potential targets for the treatment of hypercholesterolemia and atherosclerosis. Here, we demonstrate that LXRα, one of the two LXR isoforms, restricts reactivation of latent gammaherpesvirus from peritoneal cells. As gammaherpesviruses are ubiquitous oncogenic agents, LXRs may represent a targetable host factor for the treatment of poorly controlled gammaherpesvirus infection and associated lymphomagenesis.

Optimized Detection of Acute MHV68 Infection With a Reporter System Identifies Large Peritoneal Macrophages as a Dominant Target of Primary Infection

“…We note that at 14 dpi, the LANA: βlac is not well detected above background. Previous studies using this reporter virus reported LANA:βlac+ cells at less than or equal to 0.1% of splenocytes at 16 dpi (Nealy et al, 2010;Lange et al, 2019), and limiting dilution qPCR experiments have reported frequencies of less than 1% infected cells in specific cell populations in the PerC at 16 dpi (Rekow et al, 2016). Based on these data, we infer LANA: βlac+ cells are a rare but present population within the PerC at 14 days or later post infection.…”

Optimized detection of acute MHV68 infection with a reporter system identifies large peritoneal macrophages as a dominant target of primary infection

“…We note that at 14 dpi, the LANA:: βlac is not well detected above background. Previous studies using this reporter virus reported LANA::βlac+ cells at less than or equal to 0.1% of splenocytes at 16 dpi (24, 45), and limiting dilution qPCR experiments have reported frequencies of less than 1% infected cells in specific cell populations in the peritoneal cavity at 16 dpi (17). Based on these data, we infer LANA:: βlac+ cells are a rare but present population within the peritoneal cavity at 14 days or later post infection.…”

Gammaherpesvirus Usurps Host IL-17 Signaling To Support the Establishment of Chronic Infection

“…Having observed a decrease in MHV68-driven germinal center response and the frequency of MHV68-positive splenocytes, the efficiency of germinal center B cell infection was examined next using a recombinant MHV68 that expresses a fused mLANA-β-lactamase protein in latently infected cells ( 33 , 34 ). As expected, significantly fewer splenic B220 + B cells were also positive for β-lactamase activity in IL-17RA −/− mice compared to BL6 mice ( Fig.…”