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Viral infection and iron metabolism

Key Points

  • The central role of iron in fundamental processes of cellular physiology is briefly summarized. These processes must be operational for efficient viral replication, and therefore cells that are replete in iron make good homes for viruses.

  • Iron homeostasis in humans is outlined, and the action of the liver hormone hepcidin is described. Hepcidin maintains iron balance, and its synthesis is regulated by many proteins, one of which is HFE.

  • Iron overload is a risk factor for severe disease in hepatitis C virus (HCV) infection. HCV itself manipulates cellular iron transport and influences hepcidin synthesis.

  • In individuals infected with HIV-1, iron accumulation is associated with increased mortality. Iron accumulation in macrophages might favour virus replication, benefit secondary pathogens and lead to anaemia.

  • The HIV-1 protein Nef and the human cytomegalovirus (HCMV) protein US2 target HFE and therefore regulate iron transport.

  • New World haemorrhagic arenaviruses, canine and feline parvoviruses and mouse mammary tumour virus all use the host protein transferrin receptor 1 to gain entry to cells. In this way, these viruses infect activated, iron-acquiring cells, which can facilitate their replication.

  • Limiting iron availability to infected cells by iron chelators curbs the growth of HIV-1, HCMV, vaccinia virus, herpes simplex virus 1 and hepatitis B virus in vitro. In patients who are infected with HCV, iron removal ameliorates disease.

  • Together, these studies indicate that viruses directly manipulate iron homeostasis and that virally induced changes in iron transport are associated with altered disease states.

Abstract

Fundamental cellular operations, including DNA synthesis and the generation of ATP, require iron. Viruses hijack cells in order to replicate, and efficient replication needs an iron-replete host. Some viruses selectively infect iron-acquiring cells by binding to transferrin receptor 1 during cell entry. Other viruses alter the expression of proteins involved in iron homeostasis, such as HFE and hepcidin. In HIV-1 and hepatitis C virus infections, iron overload is associated with poor prognosis and could be partly caused by the viruses themselves. Understanding how iron metabolism and viral infection interact might suggest new methods to control disease.

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Figure 1: Fundamental aspects of cellular function are dependent on iron.
Figure 2: Iron transport in humans.
Figure 3: Iron homeostasis in humans.
Figure 4: Involvement of iron in the HIV-1 life cycle.
Figure 5: Viral proteins target host proteins of iron metabolism.

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Acknowledgements

We thank L. Eddowes, A. Armitage, P. Klenerman, A. McMichael and the anonymous reviewers for critical reading of the manuscript, B. Hider for helpful discussions and J. McDermid for the figure in box 2. H.D. is supported by the Beit Memorial Fellowship for Medical Research, the Medical Research Council UK and the Wellcome Trust, and A.P. is supported by the Medical Research Council UK.

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DATABASES

Entrez Genome

CPV

HBV

HCV

HIV-1

MMTV

Entrez Genome Project

Mycobacterium tuberculosis

Entrez Protein

ABCE1

Dcytb

DMT1

Gag

HCP1

HFE

Nef

Rev

Tat

Glossary

Reticuloendothelial system

The meshwork of connective tissue that contains immune cells, such as macrophages, and that surrounds tissues which are associated with the immune system, such as the spleen and lymph nodes.

Haemochromatosis

An inherited iron metabolism disorder that is caused by the chronic over-absorption of iron from the diet. The excess iron generates free radicals, which damage organs such as the liver and pancreas. Tissue damage owing to excess iron can also be a complication of other diseases, such as thalassaemia.

Acute-phase proteins

A group of proteins, including C-reactive protein and fibrinogen, the concentrations of which change in the blood in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

Erythron

The red blood cells and their developing precursors within the bone marrow.

Thalassaemia

A group of related genetic blood disorders that result from mutations in the genes that encode either the α- or β-proteins of haemoglobin and cause anaemia of varying severity.

HCV polyprotein

After cell entry, the HCV RNA genome is translated into a single 3,000 amino acid long polyprotein, which is then processed into 10 viral proteins.

Viral quasi-species

RNA viruses (including HCV and HIV-1) can be genetically heterogeneous within a single host. One viral sequence can dominate, but other complex quasi-species are also present, the genomes of which are evolving and are interrelated to varying extents.

Hypusine

An unusual amino acid that is found in all eukaryotes and is formed by the post-translational modification of lysine. The only known protein to contain hypusine is eukaryotic initiation factor 5A.

Haptoglobin

A blood plasma protein that binds free haemoglobin; haptoglobin–haemoglobin complexes are then cleared by the reticuloendothelial system. Haptoglobin is composed of two chains, the α-chain and the β-chain. The β-chain is largely invariant, but the α-chain has two major alleles, Hp1 and Hp2, and the common variants are Hp1-1, Hp2-1 and Hp2-2.

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Drakesmith, H., Prentice, A. Viral infection and iron metabolism. Nat Rev Microbiol 6, 541–552 (2008). https://doi.org/10.1038/nrmicro1930

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