Review
Microbes and Metabolism
Viral effects on metabolism: changes in glucose and glutamine utilization during human cytomegalovirus infection

https://doi.org/10.1016/j.tim.2011.04.002Get rights and content

Human cytomegalovirus (HCMV) infection causes dramatic alterations of intermediary metabolism, similar to those found in tumor cells. In infected cells, glucose carbon is not completely broken down by the tricarboxylic acid (TCA) cycle for energy; instead, it is used biosynthetically. This process requires increased glucose uptake, increased glycolysis and the diversion of glucose carbon, in the form of citrate, from the TCA cycle for use in HCMV-induced fatty acid biosynthesis. The diversion of citrate from the TCA cycle (cataplerosis) requires induction of enzymes to promote glutaminolysis, the conversion of glutamine to α-ketoglutarate to maintain the TCA cycle (anaplerosis) and ATP production. Such changes could result in heretofore uncharacterized pathogenesis, potentially implicating HCMV as a subtle cofactor in many maladies, including oncogenesis. Recognition of the effects of HCMV, and other viruses, on host cell metabolism will provide new understanding of viral pathogenesis and novel avenues for antiviral therapy.

Section snippets

The Warburg effect and tumor cell metabolism

Intermediary metabolism has been resurrected in the minds of many of us who left metabolic studies in the 1970 s to pursue the molecular biology revolution. This awakening has been spurred by the discoveries over the past five to eight years in the area of cancer biology, where metabolism has been shown to be significantly altered by oncogenesis 1, 2, 3, 4, 5, 6. Additionally, modern technologies in metabolomics (see Glossary), combined with classical biochemistry, cell biology and molecular

HCMV, potentially a subtle cofactor in many maladies

The basics of HCMV and its known pathogenesis are provided in Box 1 16, 17, 18, 19, 20. For the replicative cycle of HCMV to be successful the virus needs to alter the host cell to establish an environment that can accommodate the increased demands for nutrients, energy and macromolecular synthesis that accompany viral infection. These alterations also result in cellular stress that induces stress responses, the consequences of which could be deleterious to the viral infection; for example,

Mechanisms by which HCMV controls glycolysis, glutaminolysis and citrate cataplerosis

At this point, the mechanisms by which HCMV alters cellular metabolism are largely speculative; however, we can propose models for experimental analysis.

Why does the virus need such an increase in fatty acid synthesis?

Because HCMV is an enveloped virus, there are clearly fatty acid requirements for membranes from which the envelopes can be derived. However, examination of HCMV-infected cells suggests that membrane formation is needed for many other aspects of viral infection. It is well known that infected cells are enlarged (cytomegalia), which would require additional plasma membrane. In addition, the virion egress and assembly process appears to require a significant amount of membrane. The

Concluding remarks

HCMV infection dramatically alters cellular metabolism, and in this review we have focused on how the virus alters glucose and glutamine metabolism and fatty acid synthesis (Figure 4). Changes to glucose metabolism include increased glucose uptake through the induction of the glucose transporter GLUT4, upregulation of glycolytic enzymes and probable allosteric activation of glycolysis. Glucose is not completely broken down by the TCA cycle but maintained intact for biosynthetic purposes. This

Acknowledgments

The authors would like to thank Sherrill Adams and Alan Diehl for helpful discussions and comments on the manuscript. J. C. A. acknowledges funding through a Public Health Service Grant (R01 CA157679-01) awarded by the National Cancer Institute.

Glossary

Anaplerosis and cataplerosis
anaplerosis is the process of replenishing TCA cycle intermediates that have been removed for cataplerosis (i.e. removed from the cycle for biosynthetic reactions). For example, in HCMV-infected cells citrate is cataplerotically removed from the TCA for fatty acid synthesis, whereas glutamine is anaplerotically used to fill the TCA cycle to compensate for the lost citrate.
Glutaminolysis
the set of metabolic reactions that converts glutamine to α-ketoglutarate,

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