Host cells possess the metabolic assets required for viral infection. Recent studies indicate that control of the host’s metabolic resources is a core host-pathogen interaction. Viruses have evolved mechanisms to usurp the host’s metabolic resources, funneling them towards the production of virion components as well as the organization of specialized compartments for replication, maturation, and dissemination. Consequently, hosts have developed a variety of metabolic countermeasures to sense and resist these viral changes. The complex interplay between virus and host over metabolic control has only just begun to be deconvoluted. However, it is clear that virally induced metabolic reprogramming can substantially impact infectious outcomes, highlighting the promise of targeting these processes for antiviral therapeutic development.
In contrast to many viruses, human cytomegalovirus (HCMV) is unable to productively infect most cancer-derived cell lines. The mechanisms of this restriction are unclear. To explore this issue, we tested whether defined oncogenic alleles, including the simian virus 40 (SV40) T antigen (TAg) and oncogenic H-Ras, inhibit HCMV infection. We found that expression of SV40 TAg blocks HCMV infection in human fibroblasts, whereas the replication of a related herpesvirus, herpes simplex virus 1 (HSV-1), was not impacted. The earliest restriction of HCMV infection involves a block of viral entry, as TAg expression prevented the nuclear delivery of viral DNA and pp65. Subsequently, we found that TAg expression reduces the abundance of platelet-derived growth factor receptor ␣ (PDGFR␣), a host protein important for HCMV entry. Viral entry into TAg-immortalized fibroblasts could largely be rescued by PDGFR␣ overexpression. Similarly, PDGFR␣ overexpression in HeLa cells markedly increased the levels of HCMV gene expression and DNA replication. However, the robust production of viral progeny was not restored by PDGFR␣ overexpression in either HeLa cells or TAg-immortalized fibroblasts, suggesting additional restrictions associated with transformation and TAg expression. In TAg-expressing fibroblasts, expression of the immediate early 2 (IE2) protein was not rescued to the same extent as that of the immediate early 1 (IE1) protein, suggesting that TAg expression impacts the accumulation of major immediate early (MIE) transcripts. Transduction of IE2 largely rescued HCMV gene expression in TAg-expressing fibroblasts but did not rescue the production of infectious virions. Collectively, our data indicate that oncogenic alleles induce multiple restrictions to HCMV replication. IMPORTANCE HCMV cannot replicate in most cancerous cells, yet the causes of this restriction are not clear. The mechanisms that restrict viral replication in cancerous cells represent viral vulnerabilities that can potentially be exploited therapeutically in other contexts.Here we found that SV40 T antigen-mediated transformation inhibits HCMV infection at multiple points in the viral life cycle, including through inhibition of proper viral entry, normal expression of immediate early genes, and viral DNA replication. Our results suggest that the SV40 T antigen could be a valuable tool to dissect cellular activities that are important for successful infection, thereby potentially informing novel antiviral development strategies. This is an important consideration, given that HCMV is a leading cause of birth defects and causes severe infection in immunocompromised individuals. Human cytomegalovirus (HCMV) is a ubiquitous opportunistic betaherpesvirus that infects ϳ50 to 70% of the global population. While infection of healthy individuals is frequently resolved without severe complications, HCMV poses a major threat to immunocompromised individuals, such as AIDS patients and organ transplant recipients (1, 2). Further, HCMV is a leading cause of birth d...
Induction of Epstein-Barr virus (EBV) early antigen after treatment with various combinations of croton oil and π-butyrate was markedly inhibited by retinoids 7901, 7902, Ro 10-9359 and Ro 11-1430. Possible administration of retinoids to virus capsid antigen IgA antibody-positive individuals in high-risk areas for nasopharyngeal carcinoma to prevent EBV activation and development of this cancer is discussed.
Oncogenesis is frequently accompanied by the activation of specific metabolic pathways. One such pathway is fatty acid biosynthesis, whose induction is observed upon transformation of a wide variety of cell types. Here, we explored how defined oncogenic alleles, specifically the simian virus 40 (SV40) T antigens and oncogenic Ras 12V , affect fatty acid metabolism. Our results indicate that SV40/Ras 12V -mediated transformation of fibroblasts induces fatty acid biosynthesis in the absence of significant changes in the concentration of fatty acid biosynthetic enzymes. This oncogene-induced activation of fatty acid biosynthesis was found to be mammalian target of rapamycin (mTOR) dependent, as it was attenuated by rapamycin treatment. Furthermore, SV40/ Ras 12V -mediated transformation induced sensitivity to treatment with fatty acid biosynthetic inhibitors. Pharmaceutical inhibition of acetyl-coenzyme A (CoA) carboxylase (ACC), a key fatty acid biosynthetic enzyme, induced caspase-dependent cell death in oncogene-transduced cells. In contrast, isogenic nontransformed cells were resistant to fatty acid biosynthetic inhibition. This oncogene-induced sensitivity to fatty acid biosynthetic inhibition was independent of the cells' growth rates and could be attenuated by supplementing the medium with unsaturated fatty acids. Both the activation of fatty acid biosynthesis and the sensitivity to fatty acid biosynthetic inhibition could be conveyed to nontransformed breast epithelial cells through transduction with oncogenic Ras 12V . Similar to what was observed in the transformed fibroblasts, the Ras 12V -induced sensitivity to fatty acid biosynthetic inhibition was independent of the proliferative status and could be attenuated by supplementing the medium with unsaturated fatty acids. Combined, our results indicate that specific oncogenic alleles can directly confer sensitivity to inhibitors of fatty acid biosynthesis. IMPORTANCEViral oncoproteins and cellular mutations drive the transformation of normal cells to the cancerous state. These oncogenic alterations induce metabolic changes and dependencies that can be targeted to kill cancerous cells. Here, we find that the cellular transformation resulting from combined expression of the SV40 early region with an oncogenic Ras allele is sufficient to induce cellular susceptibility to fatty acid biosynthetic inhibition. Inhibition of fatty acid biosynthesis in these cells resulted in programmed cell death, which could be rescued by supplementing the medium with nonsaturated fatty acids. Similar results were observed with the expression of oncogenic Ras in nontransformed breast epithelial cells. Combined, our results suggest that specific oncogenic alleles induce metabolic dependencies that can be exploited to selectively kill cancerous cells. Cancerous cells frequently exhibit substantial metabolic differences from the tissues that they were derived from. These changes are widely shared and independent of their tissue of origin, highlighting a common cancer cell m...
Human cytomegalovirus (HCMV) poses serious threats to newborns and immune-compromised individuals. In contrast to most viruses studied, HCMV is unable to replicate in cancerous cells, but the mechanisms of this restriction are unclear. We explored these mechanisms by determining whether defined oncogenic alleles including the simian virus 40 (SV40) T antigens and oncogenic HRas G12V could inhibit HCMV replication. Our results show that the expression of SV40 T antigens blocks HCMV replication. In contrast, the replication of a related herpes virus, herpes simplex virus I, is not impacted by T antigen expression. The earliest restriction of HCMV infection involves a block of viral entry, as T antigen expression prevents viral tegument protein delivery. Subsequently we find that T antigen expression reduces the accumulation of platelet-derived growth factor receptor (PDGFR) alpha, a host protein that facilitates HCMV entry. Viral entry, gene expression and DNA replication could be partially rescued by PDGFR alpha over-expression. However, production of infectious viral progeny is not restored by PDGFR alpha over-expression in T antigen-expressing fibroblasts. Analysis of viral gene expression indicates that the accumulation of immediate early 2 (IE2), the major viral transcriptional activator, is inhibited by T antigen expression. Restoration of IE2 expression markedly increases downstream HCMV gene expression but not virion production, suggesting additional viral restrictions induced by T antigen. Similarly, PDGFR alpha over-expression in Hela cells markedly increases HCMV gene expression and DNA replication but not virion production. Combined, our results indicate that oncogenic alleles induce multiple restrictions to HCMV infection. Citation Format: Shihao Xu, Xenia Schafer, Joshua Munger. Expression of oncogenic alleles induces multiple blocks to HCMV infection. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A47.
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