Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells

Abstract

Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the “Warburg Effect” and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.

Hepatitis C Virus Translation Regulation

“…Concomitantly, expression of cellular proto-oncogenes including hras, c-fos, c-jun, c-myc, and vav1 was elevated under ARF/core+1 overexpression, and the number of tumors in mice overexpressing the ARF/core+1 protein during chemically induced tumorigenesis was significantly increased [245]. This indicates that HCV not only rapidly reprograms the hepatocyte metabolism to promote the Warburg effect that is a characteristic of tumor cells [11,246] but also establishes proto-oncogene expression changes that lead to cancer in the long run. Future research should also systematically search for cellular binding partners of the ARF/core+1 protein by global scale interactome and for targets of gene expression regulation by crosslink immunoprecipitation (CLIP) studies.…”

“…However, most HCV infections remain inapparent [5,6], and the virus infection can become chronic in about 60% to 70 % of all infections [7], often without being noticed. Chronic infection can, in the long run, result in liver cirrhosis and liver cancer (hepatocellular carcinoma, HCC) [8][9][10], while a metabolic reprogramming of the infected cells according to the "Warburg effect" like in cancer cells can be observed only a few days after the onset of HCV replication [11]. Moreover, inapparent replication of the virus usually results in unnoticed spread of the virus to other individuals, a fact that is a major challenge for surveillance, health care, and treatment [12].…”

Metabolic changes during respiratory syncytial virus infection of epithelial cells

“…We have found that levels of lactic acid were increased after 12 hpi (Figs 2 & 4, S1A File), indicative of a Warburg effect. Growing evidence support the idea that many DNA viruses (human papillomavirus, HCMV, EBV, KSHV, human adenovirus), but also single-stranded RNA viruses (poliovirus, dengue virus, hepatitis C virus, influenza virus) exploit aerobic glycolysis [1,3,48,49].…”

Functional characterization of SARS-CoV-2 infection suggests a complex inflammatory response and metabolic alterations

“…Metabolism node showed also a higher functional node activity in Covid-19 patients than in healthy controls. The increase in glycolysis reactions implies an increase in Krebs cycle reactions as well and therefore in ATP production, essential for the virus replication [10, 11]. The differences on the metabolism functional node suggested that a deeper analysis of metabolism, as Flux Balance Analysis, could supply more detail information.…”