Correction: Epstein–Barr virus oncoprotein–driven B cell metabolism remodeling

Abstract

The γ-herpesvirus Epstein-Barr virus (EBV) persistently infects >95% of adults worldwide and contributes to 200,000 cancers annually [1]. EBV uses latency programs to convert metabolically quiescent B lymphocytes into blasts that enter germinal centers and differentiate into memory B cells, the reservoir for lifelong infection. Over the first 3 days of infection, EBV expresses the pre-proliferation program, where particularly high levels of Epstein-Barr nuclear antigen 2 (EBNA2) and its key host target MYC induce metabolism pathways needed for B cell remodeling and proliferation (Fig 1) [1-4]. Over this period, infected cells quadruple in volume in preparation for hyperproliferation [2,5], reminiscent of remodeling that fuels germinal center centroblasts [6]. The EBV latency IIb program, comprised of 6 EBNAs and noncoding RNA (ncRNA), then supports hyperproliferation between days 4 and 7 postinfection in cell culture (Fig 1). Subsequently, cells convert to lymphoblastoid physiology, where 6 EBNAs and 2 latent membrane proteins (LMPs) further remodel host metabolism [7,8]. If left unchecked by immune surveillance, latency III causes outgrowth of lymphoblastoid cell lines (LCLs) that model posttransplant lymphoproliferative diseases (PTLDs) and central nervous system lym-phomas [1] (Fig 1). Here, we review key host metabolism pathways subverted by EBV onco-proteins, with a focus on B cell transformation. LAU : Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly: atent EBV induction of aerobic glycolysis Within 4 days of infection, EBV highly induces glucose uptake and expression of all glycolysis enzymes at the mRNA and protein levels, in particular the first and rate-limiting enzyme hexo-kinase 2 [2,4,9]. Seahorse assays confirm that EBV increases glycolytic flux [4,9], which generates lower quantities of ATP than oxidative phosphorylation (OXPHOS), but provides key building blocks for anabolic metabolism. EBNA2, the only EBV oncoprotein required for newly infected B cell outgrowth over the first 8