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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ajioka, R. S., Phillips, J. D. & Kushner, J. P. Biosynthesis of heme in mammals. Biochim. Biophys. Acta 1763, 723–736 (2006).
Hatefi, Y. The mitochondrial electron transport and oxidative phosphorylation system. Annu. Rev. Biochem. 54, 1015–1069 (1985).
Schneider-Yin, X. et al. Mutations in the iron–sulfur cluster ligands of the human ferrochelatase lead to erythropoietic protoporphyria. Blood 96, 1545–1549 (2000).
Jordan, A. & Reichard, P. Ribonucleotide reductases. Annu. Rev. Biochem. 67, 71–98 (1998).
Pang, H. et al. Crystal structure of human pirin: an iron-binding nuclear protein and transcription cofactor. J. Biol. Chem. 279, 1491–1498 (2004).
Klinge, S., Hirst, J., Maman, J. D., Krude, T. & Pellegrini, L. An iron–sulfur domain of the eukaryotic primase is essential for RNA primer synthesis. Nature Struct. Mol. Biol. 14, 875–877 (2007).
Rudolf, J., Makrantoni, V., Ingledew, W. J., Stark, M. J. & White, M. F. The DNA repair helicases XPD and FancJ have essential iron–sulfur domains. Mol. Cell 23, 801–808 (2006).
Chen, Z. Q. et al. The essential vertebrate ABCE1 protein interacts with eukaryotic initiation factors. J. Biol. Chem. 281, 7452–7457 (2006).
Umbreit, J. Iron deficiency: a concise review. Am. J. Hematol. 78, 225–231 (2005).
Schaible, U. E. & Kaufmann, S. H. Iron and microbial infection. Nature Rev. Microbiol. 2, 946–953 (2004).
Boyd, P. W. et al. Mesoscale iron enrichment experiments 1993–2005: synthesis and future directions. Science 315, 612–617 (2007).
Boyd, P. W. et al. A mesoscale phytoplankton bloom in the polar Southern Ocean stimulated by iron fertilization. Nature 407, 695–702 (2000).
Suttle, C. A. Marine viruses — major players in the global ecosystem. Nature Rev. Microbiol. 5, 801–812 (2007).
Suttle, C. A. Viruses in the sea. Nature 437, 356–361 (2005).
McCance, R. A. & Widdowson, E. M. Absorption and excretion of iron. Lancet 2, 680–684 (1937). Landmark paper in the field of iron metabolism in which the authors propose that iron balance is maintained not by altering iron excretion, but by regulating absorption of iron from the diet.
McCance, R. A. & Widdowson, E. M. The absorption and excretion of iron following oral and intravenous administration. J. Physiol. 94, 148–154 (1938).
Andrews, N. C. & Schmidt, P. J. Iron homeostasis. Annu. Rev. Physiol. 69, 69–85 (2007).
McKie, A. T. et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755–1759 (2001).
Gunshin, H. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482–488 (1997).
Shayeghi, M. et al. Identification of an intestinal heme transporter. Cell 122, 789–801 (2005).
Abboud, S. & Haile, D. J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275, 19906–19912 (2000).
Donovan, A. et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781 (2000).
McKie, A. T. et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 5, 299–309 (2000).
Vulpe, C. D. et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nature Genet. 21, 195–199 (1999).
Dautry-Varsat, A., Ciechanover, A. & Lodish, H. F. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 80, 2258–2262 (1983).
Klausner, R. D., Ashwell, G., van Renswoude, J., Harford, J. B. & Bridges, K. R. Binding of apotransferrin to K562 cells: explanation of the transferrin cycle. Proc. Natl Acad. Sci. USA 80, 2263–2266 (1983).
Ohgami, R. S. et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nature Genet. 37, 1264–1269 (2005).
Nemeth, E. & Ganz, T. Regulation of iron metabolism by hepcidin. Annu. Rev. Nutr. 26, 323–342 (2006).
Krause, A. et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480, 147–150 (2000).
Nicolas, G. et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc. Natl Acad. Sci. USA 98, 8780–8785 (2001). Serendipitous discovery of hepcidin and its link with iron homeostasis.
Park, C. H., Valore, E. V., Waring, A. J. & Ganz, T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276, 7806–7810 (2001).
Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004). Identified the mechanism of action of hepcidin, the iron regulatory hormone.
Nicolas, G. et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110, 1037–1044 (2002).
Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13, 399–408 (1996). Cloned HLA-H (later renamed HFE ), the gene that is most commonly associated with haemochromatosis.
Papanikolaou, G. et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nature Genet. 36, 77–82 (2004).
Nemeth, E., Roetto, A., Garozzo, G., Ganz, T. & Camaschella, C. Hepcidin is decreased in TFR2 hemochromatosis. Blood 105, 1803–1806 (2005).
Njajou, O. T. et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nature Genet. 28, 213–214 (2001).
Roetto, A. et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nature Genet. 33, 21–22 (2003).
Nemeth, E. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271–1276 (2004).
Peyssonnaux, C. et al. TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 107, 3727–3732 (2006).
Nemeth, E. et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101, 2461–2463 (2003).
Kulaksiz, H. et al. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J. Endocrinol. 184, 361–370 (2005).
Kowdley, K. V. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127, S79–S86 (2004).
Bacon, B. R., Tavill, A. S., Brittenham, G. M., Park, C. H. & Recknagel, R. O. Hepatic lipid peroxidation in vivo in rats with chronic iron overload. J. Clin. Invest. 71, 429–439 (1983).
Galli, A. et al. Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology 41, 1074–1084 (2005).
Poynard, T., Yuen, M. F., Ratziu, V. & Lai, C. L. Viral hepatitis C. Lancet 362, 2095–2100 (2003).
Fujita, N. et al. Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J. Gastroenterol. Hepatol. 22, 1886–1893 (2007).
Thursz, M. Iron, haemochromatosis and thalassaemia as risk factors for fibrosis in hepatitis C virus infection. Gut 56, 613–614 (2007).
Gardenghi, S. et al. Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 109, 5027–5035 (2007).
Sartori, M. et al. Heterozygous β-globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis C. Gut 56, 693–698 (2007).
Parkkila, S. et al. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc. Natl Acad. Sci. USA 94, 13198–13202 (1997).
Drakesmith, H. et al. The hemochromatosis protein HFE inhibits iron export from macrophages. Proc. Natl Acad. Sci. USA 99, 15602–15607 (2002).
Piperno, A. et al. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 110, 4096–4100 (2007). An insightful study which demonstrated that HFE couples the level of iron in the blood (transferrin saturation) to hepcidin synthesis.
Beutler, E., Felitti, V. J., Koziol, J. A., Ho, N. J. & Gelbart, T. Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359, 211–218 (2002).
Gattoni, A. et al. Role of hemochromatosis genes in chronic hepatitis C. Clin. Ter. 157, 61–68 (2006).
Nahon, P. et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 134, 102–110 (2008).
Di Bisceglie, A. M., Axiotis, C. A., Hoofnagle, J. H. & Bacon, B. R. Measurements of iron status in patients with chronic hepatitis. Gastroenterology 102, 2108–2113 (1992).
Fujita, N. & Takei, Y. Iron, hepatitis C virus, and hepatocellular carcinoma: iron reduction preaches the gospel for chronic hepatitis C. J. Gastroenterol. 42, 923–926 (2007).
Haque, S., Chandra, B., Gerber, M. A. & Lok, A. S. Iron overload in patients with chronic hepatitis C: a clinicopathologic study. Hum. Pathol. 27, 1277–1281 (1996).
Fujita, N. et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol. Med. 13, 97–104 (2007). Identified hepcidin suppression as a possible mechanism for iron overload in HCV.
Saito, H. et al. Up-regulation of transferrin receptor 1 in chronic hepatitis C: implication in excess hepatic iron accumulation. Hepatol. Res. 31, 203–210 (2005).
Takeo, M. et al. Upregulation of transferrin receptor 2 and ferroportin 1 mRNA in the liver of patients with chronic hepatitis C. J. Gastroenterol. Hepatol. 20, 562–569 (2005).
Theurl, I. et al. Iron regulates hepatitis C virus translation via stimulation of expression of translation initiation factor 3. J. Infect. Dis. 190, 819–825 (2004).
Kakizaki, S. et al. Iron enhances hepatitis C virus replication in cultured human hepatocytes. Liver 20, 125–128 (2000).
Fillebeen, C. et al. Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus. J. Biol. Chem. 280, 9049–9057 (2005).
Fillebeen, C. et al. Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J. Hepatol. 47, 12–22 (2007).
Furutani, T. et al. Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology 130, 2087–2098 (2006).
Nishina, S. et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134, 226–238 (2008).
Farci, P. et al. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 288, 339–344 (2000).
Kato, J. et al. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J. Gastroenterol. 42, 830–836 (2007). Showed that iron-reduction therapy can be beneficial in the context of HCV infection.
Stebbing, J., Gazzard, B. & Douek, D. C. Where does HIV live? N. Engl. J. Med. 350, 1872–1880 (2004).
Kaufmann, S. H. & McMichael, A. J. Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nature Med. 11, S33–S44 (2005).
McDermid, J. M. et al. Elevated iron status strongly predicts mortality in West African adults with HIV infection. J. Acquir. Immune Defic. Syndr. 46, 498–507 (2007). From a large cohort of patients with HIV-1, showed that high iron status, measured by a range of indicators, strongly predicts accelerated mortality even after adjustment for markers of inflammation and immune function.
de Monye, C., Karcher, D. S., Boelaert, J. R. & Gordeuk, V. R. Bone marrow macrophage iron grade and survival of HIV-seropositive patients. AIDS 13, 375–380 (1999).
Montaner, L. J. et al. Advances in macrophage and dendritic cell biology in HIV-1 infection stress key understudied areas in infection, pathogenesis, and analysis of viral reservoirs. J. Leukoc. Biol. 80, 961–964 (2006).
Nabel, G. & Baltimore, D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326, 711–713 (1987).
Xiong, S. et al. Signaling role of intracellular iron in NF-κB activation. J. Biol. Chem. 278, 17646–17654 (2003).
Chen, L. et al. Iron causes interactions of TAK1, p21ras, and phosphatidylinositol 3-kinase in caveolae to activate IKK kinase in hepatic macrophages. J. Biol. Chem. 282, 5582–5588 (2007).
Brady, J. & Kashanchi, F. Tat gets the “green” light on transcription initiation. Retrovirology 2, 69 (2005).
Laspia, M. F., Rice, A. P. & Mathews, M. B. HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation. Cell 59, 283–292 (1989).
Weinberger, L. S., Dar, R. D. & Simpson, M. L. Transient-mediated fate determination in a transcriptional circuit of HIV. Nature Genet. 40, 466–470 (2008).
Yang, X. et al. TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. Proc. Natl Acad. Sci. USA 94, 12331–12336 (1997).
Nekhai, S. & Jeang, K. T. Transcriptional and post-transcriptional regulation of HIV-1 gene expression: role of cellular factors for Tat and Rev. Future Microbiol. 1, 417–426 (2006).
Debebe, Z. et al. Iron chelators ICL670 and 311 inhibit HIV-1 transcription. Virology 367, 324–333 (2007).
Gao, J. & Richardson, D. R. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression. Blood 98, 842–850 (2001).
Ruhl, M. et al. Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation. J. Cell Biol. 123, 1309–1320 (1993).
Cooper, H. L., Park, M. H., Folk, J. E., Safer, B. & Braverman, R. Identification of the hypusine-containing protein hy+ as translation initiation factor eIF-4D. Proc. Natl Acad. Sci. USA 80, 1854–1857 (1983).
Kim, Y. S. et al. Deoxyhypusine hydroxylase is an Fe(II)-dependent, HEAT-repeat enzyme. Identification of amino acid residues critical for Fe(II) binding and catalysis. J. Biol. Chem. 281, 13217–13225 (2006).
Hauber, I. et al. Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. J. Clin. Invest. 115, 76–85 (2005).
Zimmerman, C. et al. Identification of a host protein essential for assembly of immature HIV-1 capsids. Nature 415, 88–92 (2002). The iron-containing protein ABCE1 was shown to have a role in HIV-1 virion assembly.
Dong, J. et al. The essential ATP-binding cassette protein RLI1 functions in translation by promoting preinitiation complex assembly. J. Biol. Chem. 279, 42157–42168 (2004).
Kispal, G. et al. Biogenesis of cytosolic ribosomes requires the essential iron–sulphur protein Rli1p and mitochondria. EMBO J. 24, 589–598 (2005).
Yarunin, A. et al. Functional link between ribosome formation and biogenesis of iron–sulfur proteins. EMBO J. 24, 580–588 (2005).
Dooher, J. E. & Lingappa, J. R. Conservation of a stepwise, energy-sensitive pathway involving HP68 for assembly of primate lentivirus capsids in cells. J. Virol. 78, 1645–1656 (2004).
Dooher, J. E., Schneider, B. L., Reed, J. C. & Lingappa, J. R. Host ABCE1 is at plasma membrane HIV assembly sites and its dissociation from Gag is linked to subsequent events of virus production. Traffic 8, 195–211 (2007).
Lingappa, J. R., Dooher, J. E., Newman, M. A., Kiser, P. K. & Klein, K. C. Basic residues in the nucleocapsid domain of Gag are required for interaction of HIV-1 gag with ABCE1 (HP68), a cellular protein important for HIV-1 capsid assembly. J. Biol. Chem. 281, 3773–3784 (2006).
Traore, H. N. & Meyer, D. The effect of iron overload on in vitro HIV-1 infection. J. Clin. Virol. 31 (Suppl. 1), 92–98 (2004).
Boelaert, J. R., Vandecasteele, S. J., Appelberg, R. & Gordeuk, V. R. The effect of the host's iron status on tuberculosis. J. Infect. Dis. 195, 1745–1753 (2007).
Orenstein, J. M., Fox, C. & Wahl, S. M. Macrophages as a source of HIV during opportunistic infections. Science 276, 1857–1861 (1997). Showed that HIV-1 can be produced in high levels from macrophages that are co-infected with other pathogens.
Knutson, M. & Wessling-Resnick, M. Iron metabolism in the reticuloendothelial system. Crit. Rev. Biochem. Mol. Biol. 38, 61–88 (2003).
Weiss, G. & Goodnough, L. T. Anemia of chronic disease. N. Engl. J. Med. 352, 1011–1023 (2005).
Lundgren, J. D. & Mocroft, A. Anemia and survival in human immunodeficiency virus. Clin. Infect. Dis. 37 (Suppl. 4), 297–303 (2003).
O'Brien, M. E. et al. Anemia is an independent predictor of mortality and immunologic progression of disease among women with HIV in Tanzania. J. Acquir. Immune Defic. Syndr. 40, 219–225 (2005).
Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001).
Schaer, D. J. et al. CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood 107, 373–380 (2006).
Delanghe, J. R. et al. Haptoglobin polymorphism, iron metabolism and mortality in HIV infection. AIDS 12, 1027–1032 (1998).
Roberts, E. S. et al. Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS. Am. J. Pathol. 162, 2041–2057 (2003).
Mulero, V., Searle, S., Blackwell, J. M. & Brock, J. H. Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin-receptor-mediated, iron uptake. Biochem. J. 363, 89–94 (2002).
Marquet, S. et al. Variants of the human NRAMP1 gene and altered human immunodeficiency virus infection susceptibility. J. Infect. Dis. 180, 1521–1525 (1999).
Chen, N. et al. HIV-1 down-regulates the expression of CD1d via Nef. Eur. J. Immunol. 36, 278–286 (2006).
Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F. & Heard, J. M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Med. 2, 338–342 (1996).
Drakesmith, H. et al. HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Proc. Natl Acad. Sci. USA 102, 11017–11022 (2005).
Nielsen, P., Degen, O., Brummer, J. & Gabbe, E. E. Long-term survival in a patient with AIDS and hereditary haemochromatosis. Eur. J. Haematol. 63, 202–204 (1999).
Hewitt, E. W. The MHC class I antigen presentation pathway: strategies for viral immune evasion. Immunology 110, 163–169 (2003).
Ben-Arieh, S. V. et al. Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J. Virol. 75, 10557–10562 (2001). The first paper to show that HFE can be a target for viral proteins.
Vahdati-Ben Arieh, S. et al. A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules. Blood 101, 2858–2864 (2003).
Parrish, C. R. Pathogenesis of feline panleukopenia virus and canine parvovirus. Baillieres Clin. Haematol. 8, 57–71 (1995).
Parker, J. S. & Parrish, C. R. Cellular uptake and infection by canine parvovirus involves rapid dynamin-regulated clathrin-mediated endocytosis, followed by slower intracellular trafficking. J. Virol. 74, 1919–1930 (2000).
Hueffer, K. & Parrish, C. R. Parvovirus host range, cell tropism and evolution. Curr. Opin. Microbiol. 6, 392–398 (2003).
Truyen, U., Evermann, J. F., Vieler, E. & Parrish, C. R. Evolution of canine parvovirus involved loss and gain of feline host range. Virology 215, 186–189 (1996).
Parker, J. S., Murphy, W. J., Wang, D., O'Brien, S. J. & Parrish, C. R. Canine and feline parvoviruses can use human or feline transferrin receptors to bind, enter, and infect cells. J. Virol. 75, 3896–3902 (2001).
Hueffer, K. et al. The natural host range shift and subsequent evolution of canine parvovirus resulted from virus-specific binding to the canine transferrin receptor. J. Virol. 77, 1718–1726 (2003).
Hueffer, K., Govindasamy, L., Agbandje-McKenna, M. & Parrish, C. R. Combinations of two capsid regions controlling canine host range determine canine transferrin receptor binding by canine and feline parvoviruses. J. Virol. 77, 10099–10105 (2003).
Bowen, M. D., Peters, C. J. & Nichol, S. T. The phylogeny of New World (Tacaribe complex) arenaviruses. Virology 219, 285–290 (1996).
Radoshitzky, S. R. et al. Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature 446, 92–96 (2007). Identified the cellular receptor that links arenaviruses with iron metabolism.
Radoshitzky, S. R. et al. Receptor determinants of zoonotic transmission of New World hemorrhagic fever arenaviruses. Proc. Natl Acad. Sci. USA 105, 2664–2669 (2008).
Flanagan, M. L. et al. New World clade B arenaviruses can use transferrin receptor 1 (TfR1)-dependent and independent entry pathways, and glycoproteins from human pathogenic strains are associated with the use of TfR1. J. Virol. 82, 938–948 (2008).
Ross, S. R., Schofield, J. J., Farr, C. J. & Bucan, M. Mouse transferrin receptor 1 is the cell entry receptor for mouse mammary tumor virus. Proc. Natl Acad. Sci. USA 99, 12386–12390 (2002).
Oldenburg, J., Reignier, T., Flanagan, M. L., Hamilton, G. A. & Cannon, P. M. Differences in tropism and pH dependence for glycoproteins from the clade B1 arenaviruses: implications for receptor usage and pathogenicity. Virology 364, 132–139 (2007).
Lebron, J. A., West, A. P. Jr & Bjorkman, P. J. The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J. Mol. Biol. 294, 239–245 (1999).
Wang, E., Albritton, L. & Ross, S. R. Identification of the segments of the mouse transferrin receptor 1 required for mouse mammary tumor virus infection. J. Biol. Chem. 281, 10243–10249 (2006).
Bastin, J., Drakesmith, H., Rees, M., Sargent, I. & Townsend, A. Localisation of proteins of iron metabolism in the human placenta and liver. Br. J. Haematol. 134, 532–543 (2006).
Mulvey, M. R., Fang, H., Holmes, C. F. & Scraba, D. G. The cellular U-particle, whose synthesis is induced by mengovirus infection, is homologous to apoferritin. Virology 198, 81–91 (1994).
Mulvey, M. R., Kuhn, L. C. & Scraba, D. G. Induction of ferritin synthesis in cells infected with Mengo virus. J. Biol. Chem. 271, 9851–9857 (1996).
Zoll, J., Melchers, W. J., Galama, J. M. & van Kuppeveld, F. J. The mengovirus leader protein suppresses alpha/beta interferon production by inhibition of the iron/ferritin-mediated activation of NF-κB. J. Virol. 76, 9664–9672 (2002).
Gu, J. M. et al. HBx modulates iron regulatory protein 1-mediated iron metabolism via reactive oxygen species. Virus Res. 133, 167–177 (2008).
Neufeld, E. J. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 107, 3436–3441 (2006).
Costagliola, D. G. et al. Dose of desferrioxamine and evolution of HIV-1 infection in thalassaemic patients. Br. J. Haematol. 87, 849–852 (1994).
Georgiou, N. A. et al. Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. J. Infect. Dis. 181, 484–490 (2000).
Sappey, C. et al. Iron chelation decreases NF-κB and HIV type 1 activation due to oxidative stress. AIDS Res. Hum. Retroviruses 11, 1049–1061 (1995).
Georgiou, N. A. et al. Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis. Eur. J. Clin. Invest. 32 (Suppl. 1), 91–96 (2002).
Romeo, A. M., Christen, L., Niles, E. G. & Kosman, D. J. Intracellular chelation of iron by bipyridyl inhibits DNA virus replication: ribonucleotide reductase maturation as a probe of intracellular iron pools. J. Biol. Chem. 276, 24301–24308 (2001). A clear demonstration of how iron chelation can inhibit virus replication.
Chouteau, P. et al. Inhibition of hepatitis B virus production associated with high levels of intracellular viral DNA intermediates in iron-depleted HepG2.2.15 cells. J. Hepatol. 34, 108–113 (2001).
Crowe, W. E., Maglova, L. M., Ponka, P. & Russell, J. M. Human cytomegalovirus-induced host cell enlargement is iron dependent. Am. J. Physiol. Cell Physiol. 287, C1023–C1030 (2004).
Cinatl, J. Jr et al. In vitro inhibition of human cytomegalovirus replication by desferrioxamine. Antiviral Res. 25, 73–77 (1994).
Bernhardt, P. V. Coordination chemistry and biology of chelators for the treatment of iron overload disorders. Dalton Trans. 3214–3220 (2007).
Weinberg, E. D. Iron withholding: a defense against viral infections. Biometals 9, 393–399 (1996).
Beck, M. A. Selenium and host defence towards viruses. Proc. Nutr. Soc. 58, 707–711 (1999).
Beck, M. A. Selenium and vitamin E status: impact on viral pathogenicity. J. Nutr. 137, 1338–1340 (2007).
Beck, M. A., Shi, Q., Morris, V. C. & Levander, O. A. Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nature Med. 1, 433–436 (1995). Showed how viruses can evolve owing to changes in the oxidant status of the host.
Nelson, H. K. et al. Host nutritional selenium status as a driving force for influenza virus mutations. FASEB J. 15, 1846–1848 (2001).
Li, W. & Beck, M. A. Selenium deficiency induced an altered immune response and increased survival following influenza A/Puerto Rico/8/34 infection. Exp. Biol. Med. (Maywood) 232, 412–419 (2007).
Beck, M. A., Shi, Q., Morris, V. C. & Levander, O. A. Benign coxsackievirus damages heart muscle in iron-loaded vitamin E-deficient mice. Free Radic. Biol. Med. 38, 112–116 (2005).
McDermid, J. M. & Prentice, A. M. Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP1 (SLC11A1) on host–pathogen interactions in tuberculosis and HIV. Clin. Sci. (Lond.) 110, 503–524 (2006).
Salhi, Y. et al. Serum ferritin, desferrioxamine, and evolution of HIV-1 infection in thalassemic patients. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 18, 473–478 (1998).
Salmon-Ceron, D. et al. Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia. J. Infect. Dis. 172, 656–664 (1995).
Gordeuk, V. R. et al. The association of serum ferritin and transferrin receptor concentrations with mortality in women with human immunodeficiency virus infection. Haematologica 91, 739–743 (2006).
Friis, H. et al. Iron, haptoglobin phenotype, and HIV-1 viral load: a cross-sectional study among pregnant Zimbabwean women. J. Acquir. Immune Defic. Syndr. 33, 74–81 (2003).
Kupka, R. et al. Iron status is an important cause of anemia in HIV-infected Tanzanian women but is not related to accelerated HIV disease progression. J. Nutr. 137, 2317–2323 (2007).
Simonart, T. et al. Iron as a potential co-factor in the pathogenesis of Kaposi's sarcoma? Int. J. Cancer 78, 720–726 (1998).
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.
- 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.
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.
The red blood cells and their developing precursors within the bone marrow.
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.
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.
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.
About this article
Cite this article
Drakesmith, H., Prentice, A. Viral infection and iron metabolism. Nat Rev Microbiol 6, 541–552 (2008). https://doi.org/10.1038/nrmicro1930
The U-shaped association of serum iron level with disease severity in adult hospitalized patients with COVID-19
Scientific Reports (2021)
Nature Biotechnology (2021)
Nature Geoscience (2021)
Learning from pathophysiological aspects of COVID-19 clinical, laboratory, and high-resolution CT features: a retrospective analysis of 128 cases by disease severity
Emergency Radiology (2021)
Evaluation of iron, ferritin, copper, and ceruloplasmin along with proviral load in human T lymphotropic virus type 1–associated myelopathy
Journal of NeuroVirology (2021)