REVIEW Metabolic reprogramming: a hallmark of viral oncogenesis P Lévy 1 and B Bartosch 1,2 More than 1 in 10 cases of cancer in the world are due to chronic viral infections. Viruses induce oncogenesis by targeting the same pathways known to be responsible for neoplasia in tumor cells, such as control of cell cycle progression, cell migration, proliferation and evasion from cell death and the host’s immune defense. In addition, metabolic reprogramming has been identified over a century ago as a requirement for growth of transformed cells. Renewed interest in this topic has emerged recently with the discovery that basically all metabolic changes in tumor cells are finely orchestrated by oncogenes and tumor suppressors. Indeed, cancer cells activate biosynthetic pathways in order to provide them with sufficient levels of energy and building blocks to proliferate. Interestingly, viruses introduce into their host cells similar metabolic adaptations, and importantly, it seems that they depend on these changes for their persistence and amplification. The central carbon metabolism, for example, is not only frequently altered in tumor cells but also modulated by human papillomavirus, hepatitis B and C viruses, Epstein–Barr virus and Kaposi’s Sarcoma-associated virus. Moreover, adenoviruses (Ad) and human cytomegalovirus, which are not directly oncogenic but present oncomodulatory properties, also divert cellular metabolism in a tumor cell-like mnner. Thus, metabolic reprogramming appears to be a hallmark of viral infection and provides an interesting therapeutic target, in particular, for oncogenic viruses. Therapeutic targeting of metabolic pathways may not only allow to eliminate or control the viral infection but also to prevent virus-induced carcinogenesis. Oncogene (2016) 35, 4155–4164; doi:10.1038/onc.2015.479; published online 21 December 2015 INTRODUCTION According to the latest estimations of the International Agency for Research on Cancer, the global burden of human cancers caused by viral infections reaches up to 11% of cancer cases worldwide. 1 Direct oncogenic alterations by insertions of viral DNA into the host cell genome are rare events. Oncogenic viruses rather promote cancer by inducing cellular alterations in the context of long-lasting, chronic infections. 2 Like any type of oncogenic mechanism, viral-induced oncogenesis is a multistep process that requires the acquisition of all the cellular features responsible for the tumor phenotype, as originally described in the ‘hallmarks of cancer’, by Weinberg and Hanahan in 2000 3 and updated in 2011. 4 One of these key requirements is a metabolic reprogramming, which is intrinsically linked to deregulated cellular energetics. The interplay between tumorigenesis and metabolism was first described with the pioneer work of Otto Warburg in the 1920s 5 but has been widely overlooked until the recent discovery that almost all oncogenic pathways are involved in the control of metabolism. 6 Today, the studies deciphering the close links between metabolic alterations and cancer are flourishing and substantially contribute to our understanding of the forces driving oncogenesis. As intracellular parasites, viruses depend on the metabolism of infected cells to proliferate. Indeed, viruses acquire both the energy and the building blocks needed to synthetize progeny virions from their host. In order to avoid metabolic exhaustion, viruses manipulate metabolic pathways and associated signaling cascades probably in order to provide sufficient resources to support optimal virion production. Although this applies to many viruses, the degree of metabolic reprogramming varies from one virus to another. In this review, we describe how viruses induce persistent modifications of the host cell’s metabolism and how these modifications contribute to cellular transformation. We recapitulate the main aspects of metabolic reprogramming and associated cell signaling that occur in cancer cells and then review the known metabolic alterations linked to infections with oncoviruses. PART I. METABOLIC REPROGRAMMING IN CANCER The Warburg effect The first investigations on cancer metabolism date back to the pioneer work of Otto Warburg in the 1920s. 5 This German scientist was the first to observe that tumor tissues metabolize through glycolysis about 10-fold more glucose to lactate than normal tissues, even in the presence of O 2 . In 1972, the term ‘Warburg effect’ was coined to allude to this increase in aerobic glycolysis in cancer cells. 7 However, contrary to the idea that mitochondria are inactive in tumors, there is now compelling evidence that most cancer cells exhibit increased glucose uptake which is then channeled into intermediate pathways and concomitantly retain mitochondrial tricarboxylic acid (TCA) cycle activity and oxidative phosphorylation (OXPHOS). 8–12 The advantage for tumor cells is the concomitant generation of sufficient amounts of ATP as well as metabolic precursors to allow increased proliferation. Indeed, both glycolysis and mitochondrial metabolism are central sources of energy and precursors for the biosynthetic pathways required for cancer cell proliferation (Figure 1a). Increased amounts of glycolytic intermediates provide the precursors required for nucleotide, amino acid and lipid synthesis as well as for cellular 1 Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France and 2 DevWeCan Laboratories of Excellence Network (Labex), Lyon, France. Correspondence: Dr B Bartosch, Inserm U1052, Cancer Research Center of Lyon, University of Lyon, 151 Cours Albert Thomas, Lyon 69434, France. E-mail: Birke.Bartosch@inserm.fr Received 26 August 2015; revised 11 November 2015; accepted 14 November 2015; published online 21 December 2015 Oncogene (2016) 35, 4155 – 4164 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0950-9232/16 www.nature.com/onc