Hepatitis C virus infection triggers a tumor‐like glutamine metabolism

Abstract

Chronic infection with hepatitis C virus (HCV) is one of the main causes of hepatocellular carcinoma. However, the molecular mechanisms linking the infection to cancer development remain poorly understood. Here we used HCV‐infected cells and liver biopsies to study how HCV modulates the glutaminolysis pathway, which is known to play an important role in cellular energetics, stress defense, and neoplastic transformation. Transcript levels of glutaminolytic factors were quantified in Huh7.5 cells or primary human hepatocytes infected with the Japanese fulminant hepatitis 1 HCV strain as well as in biopsies of chronic HCV patients. Nutrient deprivation, biochemical analysis, and metabolite quantification were performed with HCV–infected Huh7.5 cells. Furthermore, short hairpin RNA vectors and small molecule inhibitors were used to investigate the dependence of HCV replication on metabolic changes. We show that HCV modulates the transcript levels of key enzymes of glutamine metabolism in vitro and in liver biopsies of chronic HCV patients. Consistently, HCV infection increases glutamine use and dependence. We finally show that inhibiting glutamine metabolism attenuates HCV infection and the oxidative stress associated with HCV infection. Conclusion: Our data suggest that HCV establishes glutamine dependence, which is required for viral replication, and, importantly, that glutamine addiction is a hallmark of tumor cells. While HCV induces glutaminolysis to create an environment favorable for viral replication, it predisposes the cell to transformation. Glutaminolytic enzymes may be interesting therapeutic targets for prevention of hepatocarcinogenesis in chronic hepatitis C. (Hepatology 2017;65:789‐803).

Metabolic Reprogramming of Host Cells in Response to Enteroviral Infection

“…Additionally, DM-αKG treatment partially substituted for glutamine in supporting viral replication. In agreement with this, glutaminolysis is upregulated in adenovirus, human cytomegalovirus (HCMV)-, hepatitis C virus (HCV)-, and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells [41][42][43]. The changes in other TCA intermediates are also noteworthy.…”

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

“…[276][277][278][279][280]287 Consistent with these observations, deficiency of Blimp-1, another transcription factor and regulator of plasma cell differentiation, was essential to antagonize BCL-6-dependent repression of glycolytic programming. 30 Blimp-1 is also critical in terminal differentiation of CD8 T cells to CTL in response to IAV. 31 Moreover, Blimp-1-deficient CD8 T cells had weakened transcriptional programs necessary for effector functions and impaired migration to the influenza infection site.…”

“…27 IAV and hepatitis C virus (HCV) depend on c-Myc and GLS for viral replication. [28][29][30] Compared to glycolysis, less is known about the effect of RNA viruses on the TCA cycle. However, IAV and human metapneumovirus (hMPV) infection of human airway cells significantly reduced the expression of TCA cycle enzymes and ATP output.…”

An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism

“…(HCV) triggers tumorlike glutamine metabolism in hepatocytes (5). Although some host-and virusencoded microRNAs have been shown to partly mediate these alterations of metabolic pathways (6), the molecular mechanisms involved are still largely elusive-in particular, how viruses target and regulate the host metabolic network for replication and escape from host defenses.…”