Background: Hepcidin is the principal regulator of iron absorption and its tissue distribution. Its correlation with iron homeostasis in individuals infected with human immunodeficiency virus type-1 (HIV-1) treated with different regimens of highly active antiretroviral therapy (HAART) was investigated. Methods: Serum hepcidin levels were determined in 448 volunteers. Of these, 372 were HIV-1-infected individuals, and 93 did not receive HAART (ART-na ï ve) while 279 received HAART consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI-based) and protease inhibitors (PI-based); both were used in association with a nucleoside reverse transcriptase inhibitor (NRTI). Seventy-six additional HIV-1 seronegative individuals were enrolled in the study. The following parameters were quantified: hematological parameters, iron biomarkers and markers of infection (CD4+ and CD8+ T-cells), and HIV-1 RNA (viral load). Results: Serum hepcidin, iron and ferritin levels, as well as the marker of infection, CD4+ T-cells, were significantly lower in the ART-na ï ve group compared with other groups. Additionally, transferrin saturation, iron binding capacity, hemoglobin level and erythrocyte level were not significantly different, and anemia was not observed in the different groups. Conclusions: HIV-1 infection affected serum hepcidin, iron and ferritin levels in the ART-na ï ve group, and the different HAART regimens restored the levels of hepcidin and iron homeostasis in HIV-1-infected individuals who have undetectable HIV-1 RNA levels.
Ganz, T. (2007) Molecular Control Iron Transport. Journal of the American Society of Nephrology, 18, 394-400. http://dx.doi.org/10.1681/ASN.2006070802
Coyne, D.W. (2011) Hepcidin: Clinical Utility as a Diagnostic Tool and Therapeutic Target. Kidney International, 80, 240-244. http://dx.doi.org/10.1038/ki.2011.141
Babitt, J.L. and Lin, H.Y. (2010) Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD. American Journal of Kidney Diseases, 55, 726-741. http://dx.doi.org/10.1053/j.ajkd.2009.12.030
Roy, C.N., Mak, H.H., Akpan, I., Losyev, G., Zurakowski, D. and Andrews, N.C. (2007) Hepcidin Antimicrobial Peptide Transgenicmice Exhibit Features of the Anemia of Inflammation. Blood, 109, 4038-4044. http://dx.doi.org/10.1182/blood-2006-10-051755
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B.K. and Ganz, T. (2004) IL-6 Mediates Hypoferremia of Inflammation by Inducing the Synthesis of the Iron Regulatory Hormone Hepcidin. The Journal of Clinical Investigation, 113, 1271-1276. http://dx.doi.org/10.1172/JCI200420945
Donovan, A., Lima, C.A., Pinkus, J.L., Zon, L.I., Robine, S. and Andrews, N.C. (2005) The Iron Exporter Ferroportin/Slc40a1 Is Essential for Iron Homeostasis. Cell Metabolism, 1, 191-200. http://dx.doi.org/10.1016/j.cmet.2005.01.003
Nemeth, E. and Ganz, T. (2006) Regulation of Iron Metabolism by Hepcidin. Annual Review of Nutrition, 26, 323-342. http://dx.doi.org/10.1146/annurev.nutr.26.061505.111303
Ford, B.A., Eby, C.S., Scott, M.G. and Coyne, D.W. (2010) Intra-Individual Variability in Serum Hepcidin Precludes Its Use as a Marker of Iron Status in Hemodialysis Patients. Kidney International, 78, 769-773. http://dx.doi.org/10.1038/ki.2010.254
Coyne, D. (2006) Iron Indices: What Do They Really Mean? Kidney International, 69, S4-S8. http://dx.doi.org/10.1038/sj.ki.5000404
Lee, P., Peng, H., Gelbart, T., Wang, L. and Beutler, E. (2005) Regulation of Hepcidin Transcription by Interleukin-1 and Interleukin-6. Proceedings of the National Academy of Sciences of the United States of America, 102, 1906-1910. http://dx.doi.org/10.1073/pnas.0409808102
Ganz, T. (2002) The Role of Hepcidin in Iron Sequestration during Infections and in the Pathogenesis of Anemia of Chronic Disease. Israel Medical Association Journal, 4, 1043-1045.
McDermid, J.M., Jaye, A., Schim van der Loeff, M.F., Todd, J., Bates, C., Austin, S., Jeffries, D., Awasana, A.A., Whitlex, A.A. and Prentice, A. (2007) Elevated Iron Status Strongly Predicts Mortality in West African Adults with HIV Infection. Journal of Acquired Immune Deficiency Syndromes, 46, 498-507. http://dx.doi.org/10.1097/QAI.0b013e31815b2d4b
Xu, M., Kashanchi, F., Foster, A., Rotimi, J., Turner, W., Gordeuk, V.R. and Nekhai, S. (2010) Hepcidin Induces HIV-1 Transcription Inhibited by Ferroportin. Retrovirology, 7, 104. http://dx.doi.org/10.1186/1742-4690-7-104
Gordeuk, V.R., Delanghe, J.R., Langlois, M.R. and Boelaert, J.R. (2001) Iron Status and the Outcome of HIV Infection: An Overview. Journal of Clinical Virology, 20, 111-115. http://dx.doi.org/10.1016/s1386-6532(00)00134-7
Rawat, R., Humphrey, J.H., Ntozini, R., Mutasa, K., Iliff, P.J. and Stoltzfus, R.J. (2009) Elevated Iron Stores Are Associated with HIV Disease Severity and Mortality among Postpartum Women in Zimbabwe. Public Health Nutrition, 12, 1321-1329. http://dx.doi.org/10.1017/S136898000800390X
Dubé, M.P., Lipshultz, S.E., Fichtenbaum, C.J., Greenberg, R., Schecter, A.D. and Fisher, S.D. (2008) Effects of HIV Infection and Antiretroviral Therapy on the Heart and Vasculature. Circulation, 118, e36-e40. http://dx.doi.org/10.1161/CIRCULATIONAHA.107.189625
da Cunha, J., Ferreira Maselli, L.M., Treitinger, A., Monteiro, A.M., Gidlund, M., Maranhão, R.C., Spada, C. and Bydlowski, S.P. (2013) Serum Levels of IgG Antibodies against Oxidized LDL and Atherogenic Indices in HIV-1-Infected Patients Treated with Protease Inhibitors. Clinical Chemistry and Laboratory Medicine, 51, 371-378. http://dx.doi.org/10.1515/cclm-2012-0225
Savès, M., Morlat, P., Chêne, G., Peuchant, E., Pellegrin, I., Bonnet, F., Bernard, N., Lacoste, D., Salamon, R. and Beylot, J. (2001) Prognostic Value of Plasma Markers of Immune Activation in Patients with Advanced HIV Disease Treated by Combination Antiretroviral Therapy. Clinical Immunology, 99, 347-352. http://dx.doi.org/10.1006/clim.2001.5033
Maselli, L.M.F., da Cunha, J., Gutierrez, E.B., Maranhão, R.C., Spada, C. and Bydlowski, S.P. (2014) Human Paraoxonase-1 Activity Is Related to the Number of CD4+ T-Cells and Is Restored by Antiretroviral Therapy in HIV-1-Infected Individuals. Disease Markers, 2014, Article ID: 480201.
Wisaksana, R., de Mast, Q., Alisjahbana, B., Jusuf, H., Sudjana, P., Indrati, A.R., Sumantri, R. Swinkels, D., van Crevel, R. and van der Ven, A. (2013) Inverse Relationship of Serum Hepcidin Levels with CD4 Cell Counts in HIV- Infected Patients Selected from an Indonesian Prospective Cohort Study. PLoS ONE, 8, e79904. http://dx.doi.org/10.1371/journal.pone.0079904
Boelaert, J.R., Vandecasteele, S.J., Appelberg, R. and Gordeuk, V.R. (2007) The Effect of the Host’s Iron Status on Tuberculosis. The Journal of Infectious Diseases, 195, 1745-1753. http://dx.doi.org/10.1086/518040
Sow, F.B., Florence, W.C., Satoskar, A.R., Schlesinger, L.S., Zwilling, B.S. and Lafuse, W.P. (2007) Expression and Localization of Hepcidin in Macrophages: A Role in Host Defense against Tuberculosis. Journal of Leukocyte Biology, 82, 934-945. http://dx.doi.org/10.1189/jlb.0407216
Kanda, J., Mizumoto, C., Kawabata, H., Tsuchida, H., Tomosugi, N., Matsuo, K. and Uchiyama, T. (2008) Serum Hepcidin Level and Erythropoietic Activity after Hematopoietic Stem Cell Transplantation. Haematologica, 93, 1550- 1554. http://dx.doi.org/10.3324/haematol.12399
Pak, M., Lopez, M.A., Gabayan, V., Ganz, T. and Rivera, S. (2006) Suppression of Hepcidin during Anemia Requires Erythropoietic Activity. Blood, 108, 3730-3735. http://dx.doi.org/10.1182/blood-2006-06-028787
Maldarelli, F., Palmer, S., King, M.S., Wiegand, A., Polis, M.A., Mican, J., Kovacs, J.A., Davey, R.T., Rock-Kress, D., Dewar, R., Liu, S., Metcalf, J.A., Rehm, C., Brun, S.C., Hanna, G.J., Kempf, D.J., Coffin, J.M. and Mellors, J.W. (2007) ART Suppresses Plasma HIV-1 RNA to a Stable Set Point Predicted by Pretherapy Viremia. PLoS Pathogens, 3, e46. http://dx.doi.org/10.1371/journal.ppat.0030046
Deere, J.D., Kauffman, R.C., Cannavo, E., Higgins, J., Villalobos, A., Adamson, L., Schinazi, R.F., Luciw, P.A. and North, T.W. (2014) Analysis of Multiply Spliced Transcripts in Lymphoid Tissue Reservoirs of Rhesus Macaques Infected with RT-SHIV during HAART. PLoS ONE, 9, e87914. http://dx.doi.org/10.1371/journal.pone.0087914
Finzi, D., Blankson, J., Siliciano, J.D., Margolick, J.B., Chadwick, K., Pierson, T., Smith, K., Lisziewicz, J., Lori, F., Flexner, C., Quinn, T.C., Chaisson, R.E., Rosenberg, E., Walker, B., Gange, S., Gallant, J. and Siliciano, R.F. (1999) Latent Infection of CD4+ T Cells Provides a Mechanism for Lifelong Persistence of HIV-1, even in Patients on Effective Combination Therapy. Nature Medicine, 5, 512-517. http://dx.doi.org/10.1038/8394
Chun, T.W., Engel, D., Berrey, M.M., Shea, T., Corey, L. and Fauci, A.S. (1998) Early Establishment of a Pool of Latently Infected, Resting CD4+ T Cells during Primary HIV-1 Infection. Proceedings of the National Academy of Sciences of the United States of America, 95, 8869-8873. http://dx.doi.org/10.1073/pnas.95.15.8869
Lassen, K., Han, Y., Zhou, Y., Siliciano, J. and Siliciano, R.F. (2004) The Multifactorial Nature of HIV-1 Latency. Trends in Molecular Medicine, 10, 525-531. http://dx.doi.org/10.1016/j.molmed.2004.09.006
Chun, T.W., Carruth, L., Finzi, D., Shen, X., DiGiuseppe, J.A., Taylor, H., Hermankova, M., Chadwick, K., Margolick, J., Quinn, T.C., Kuo, Y.H., Brookmeyer, R., Zeiger, M.A., Barditch-Crovo, P. and Siliciano, R.F. (1997) Quantification of Latent Tissue Reservoirs and Total Body Viral Load in HIV-1 Infection. Nature, 387, 183-188. http://dx.doi.org/10.1038/387183a0
Aweeka, F.T., Mak, M., Al-Uzri, A., Peter, K., Dett, C., Franco, J., Affrime, M., Guerciolini, R., Cutler, D.L., Kahn, J. and Gambertoglio, J.G. (1995) Oral and Intravenous Zidovudine Pharmacokinetics: The Effect of Granulocyte-Ma- crophage Colony Stimulating Factor. The Journal of Clinical Pharmacology, 35, 856-864. http://dx.doi.org/10.1002/j.1552-4604.1995.tb04130.x
Hill, A. and Sawyer, W. (2009) Effects of Nucleoside Reverse Transcriptase Inhibitor Backbone on the Efficacy of First-Line Boosted Highly Active Antiretroviral Therapy Based on Protease Inhibitors: Meta-Regression Analysis of 12 Clinical Trials In 5168 Patients. HIV Medicine, 10, 527-535. http://dx.doi.org/10.1111/j.1468-1293.2009.00724.x
Fleming, R.E. and Ponka, P. (2012) Iron Overload in Human Disease. New England Journal of Medicine, 366, 348-359.http://dx.doi.org/10.1056/NEJMra1004967
Hentze, M.W., Muckenthaler, M.U., Galy, B. and Camaschella, C. (2010) Two to Tango: Regulation of Mammalian Iron Metabolism. Cell, 142, 24-38. http://dx.doi.org/10.1016/j.cell.2010.06.028
Ramos, E., Kautz, L., Rodriguez, R., Hansen, M., Gabayan, V., Ginzburg, Y., Roth, M.P., Nemeth, E. and Ganz, T. (2011) Evidence for Distinct Pathways of Hepcidin Regulation by Acute and Chronic Iron Loading in Mice. Hepatology, 53, 1333-1341. http://dx.doi.org/10.1002/hep.24178
May, M., Sterne, J.A., Sabin, C., Costagliola, D., Justice, A.C., Thiébaut, R., Gill, J., Phillips, A., Reiss, P., Hogg, R., Ledergerber, B., D’Arminio Monforte, A., Schmeisser, N., Staszewski, S. and Egger, M. (2007) Prognosis of HIV-1-Infected Patients up to 5 Years after Initiation of HAART: Collaborative Analysis of Prospective Studies. AIDS, 21, 1185-1197. http://dx.doi.org/10.1097/QAD.0b013e328133f285