Understanding Metabolic Pathway Rewiring by Oncogenic Gamma Herpesvirus

Abstract

Gamma herpesviruses, including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are key contributors to the development of various cancers through their ability to manipulate host cellular pathways. This review explores the intricate ways these viruses rewire host metabolic pathways to sustain viral persistence and promote tumorigenesis. We look into how EBV and KSHV induce glycolytic reprogramming, alter mitochondrial function, and remodel nucleotide and amino acid metabolism, highlighting the crucial role of lipid metabolism in these oncogenic processes. By understanding these metabolic alterations, which confer proliferative and survival advantages to the virus-infected cells, we can identify potential therapeutic targets and develop innovative treatment strategies for gamma herpesvirus-associated malignancies. Ultimately, this review underscores the critical role of metabolic reprogramming in gamma herpesvirus oncogenesis and its implications for precision medicine in combating virus-driven cancers.

Keywords: EBV; KSHV; Metabolic reprogramming; metabolic therapeutics; oncogenic virus.

Fig. 1. Glycolytic and mitochondrial reprogramming by gamma herpesviruses.

EBV and KSHV modulate numerous signaling pathways impacting glycolytic and mitochondrial metabolism. The EBV-encoded latent gene product, LMP1, influences glucose metabolism via several pathways, including mTOR. Similarly, KSHV infection affects glucose metabolism by regulating certain transcription factors, such as HIF1, which activates glycolytic enzymes. Additionally, EBV's LMP1, LMP2A, and EBNA2 are involved in the regulation of OXPHOS and mitochondrial fission. KSHV infection further induces vIRF1-mediated mitophagy. Green dashed lines indicate activation of transcription or activity, whereas red solid lines indicate inhibition of transcription or activity.

Fig. 2. Regulation nucleotide metabolism by gamma herpesviruses.

Schematic representation of EBV and KSHVmediated alterations in nucleotide metabolic pathways. EBV's LMP1 and EBNA2 upregulate CTPS enzyme expression through NF-κB and MYC. Furthermore, increased expression of TYMS and SHMT1 is observed in EBV-associated NPC. KSHV's vCyclin enhances CAD enzyme activation, subsequently activating the pyrimidine synthesis pathway, and KSHV's ORF2 functions as viral DHFR. Green dashed lines indicate activation of transcription or activity, whereas red solid lines indicate inhibition of transcription or activity.

Fig. 3. Alteration of amino acid metabolism by gamma herpesviruses.

This figure illustrates key disruptions in amino acid metabolism in EBV- and KSHV-associated cancers. KSHV upregulates the glutamine transporter SLC1A5 and glutaminase, driving glutaminolysis to fuel the TCA cycle, which is vital for cell survival. Additionally, KSHV-encoded microRNA enhances the expression of the cystine/glutamate antiporter xCT, facilitating cystine import for glutathione synthesis and protecting cells from oxidative stress. EBV impacts methionine metabolism by modulating MAT2A and AHCY, influencing viral DNA and histone methylation, and altering viral gene expression. Moreover, EBV-induced overexpression of arginase-1 and IDO depletes arginine and tryptophan, impairing T cell function and promoting immune evasion.

Fig. 4. Alteration of lipid metabolism by gamma herpesviruses.

This figure illustrates the crucial pathways and molecules involved in lipid metabolism in EBV and KSHV-associated cancers. For EBV, BRLF1 enhances FAS gene expression through the p38 kinase pathway, while LMP1 increases FASN expression via the SREBP-1 and USP2a, leading to increased lipid synthesis and the formation of lipid droplets. EBV further regulate lipid metabolism, supporting nasopharyngeal carcinoma (NPC) growth, with EBNA2 also inducing lipogenesis through epigenetic modifications on ATF4 promoter. LMP2A promotes lipid accumulation by inhibiting adipose triglyceride lipase (ATGL), resulting in lipid droplet accumulation. In KSHV, peroxisomal lipid metabolism is crucial for maintaining latent infection, with FABP regulation playing significant roles in the viral life cycle.