Abstract
Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections in >95% of adults worldwide and are associated with several cancers. We have shown that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection remains poorly understood. Extracellular cholesterol is carried in the serum by several lipoproteins, including low-density lipoproteins (LDL). The LDL receptor (LDL-R) mediates the endocytosis of these cholesterol-rich LDL particles into the cell, thereby supplying the cell with cholesterol. We found that LDL-R expression attenuates gammaherpesvirus replication during the early stages of the replication cycle, as evident by increased viral gene expression in LDL-R-/- primary macrophages. This was not observed in primary fibroblasts, indicating that the antiviral effects of LDL-R are cell type specific. Increased viral gene expression in LDL-R-/- primary macrophages was due to increased activity of the endogenous cholesterol synthesis pathway. Intriguingly, despite type I interferon-driven increase in LDL-R mRNA levels in infected macrophages, protein levels of LDL-R continually decreased over the single cycle of viral replication. Thus, our study has uncovered an intriguing tug of war between the LDL-R-driven antiviral effect on cholesterol metabolism and the viral targeting of the LDL-R protein. IMPORTANCE LDL-R is a cell surface receptor that mediates the endocytosis of cholesterol-rich low-density lipoproteins, allowing cells to acquire cholesterol exogenously. Several RNA viruses usurp LDL-R function to facilitate replication; however, the role of LDL-R in DNA virus infection remains unknown. Gammaherpesviruses are double-stranded DNA viruses that are associated with several cancers. Here, we show that LDL-R attenuates gammaherpesvirus replication in primary macrophages by decreasing endogenous cholesterol synthesis activity, a pathway known to support gammaherpesvirus replication. In response, LDL-R protein levels are decreased in infected cells to mitigate the antiviral effects, revealing an intriguing tug of war between the virus and the host.