Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Mononuclear Blood Cells by the Iron Chelators Deferoxamine, Deferiprone, and Bleomycin

Georgiou, Niki; Bruggen, Tjomme van der; Oudshoorn, Maroeska; Nottet, Hans S.L.M.; Marx, Joannes J.M.; Asbeck, B. S. Van

doi:10.1086/315223

Cited by 95 publications

(78 citation statements)

References 41 publications

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“…In addition, HIV-1 can induce direct tubular damage, and these changes may affect the tubular reabsorption and/or catabolism of filtered iron containing proteins, leading to the release and accumulation of soluble iron (Fe 2ϩ ) in renal tubules. Soluble iron is able to catalyze the formation of radical oxygen species (ROS) (35)(36)(37)(38)(39) and can also enhance the replication of HIV-1 (40) in macrophages that are recruited to these renal injury sites, causing further renal tubular injury.…”

Section: Discussionmentioning

confidence: 99%

Iron-Related Proteins

Soler-García¹,

Johnson²,

Hathout³

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background: Because of the risk of performing renal biopsies in children with co-morbid conditions, we carried out this study to identify candidate protein biomarkers in the urine of HIV-infected children with renal disease.Design, setting, participants & measurements: Urine samples from HIV-infected children with biopsy proven HIVnephropathy (HIVAN; n ‫؍‬ 4), HIV-associated Hemolytic Uremic Syndrome (HIV-HUS; n ‫؍‬ 2), or no renal disease (n ‫؍‬ 3) were analyzed by two-dimensional electrophoresis (2-DE) and proteomic methods. Positive findings were confirmed in HIVinfected children with (n ‫؍‬ 20) and without (n ‫؍‬ 10) proteinuria using commercially available assays.Results: By 2-DE analysis, a single urine marker was not sufficient to distinguish children with HIVAN from the others. High urine levels of ␤ 2 -microglobulin and retinol-binding protein (RBP) suggested the presence of tubular injury. In addition, we found elevated urine levels of iron and the iron-related proteins, transferrin, hemopexin, haptoglobin, lactoferrin, and neutrophil gelatinase-associated lipocalin (NGAL), in children with HIVAN and HIV-HUS. Furthermore, we detected a significant accumulation of iron in the urine and kidneys of HIV-transgenic (Tg) rats with renal disease.Conclusion: These findings suggest that iron and iron-related proteins might be promising candidate urine biomarkers to identify HIV-infected children at risk of developing HIVAN and HIV-HUS. Moreover, based on the results of previous studies, we speculate that the release or accumulation of iron in the kidney of HIV-infected children may contribute to the rapid progression of their renal disease, and could become a new therapeutic target against HIVAN and HIV-HUS.

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Section: Discussionmentioning

confidence: 99%

Iron-Related Proteins

Soler-García¹,

Johnson²,

Hathout³

et al. 2009

Clinical Journal of the American Society of Nephrology

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“…In vitro studies demonstrated that iron enhances hepatitis C virus replication in cultured human hepatocytes (15). Replication of human immunodeficiency virus type 1 can be influenced by iron, as demonstrated by the fact that iron chelators inhibit virus replication (13,32). Iron chelators also inhibit CMV infection and CMV-induced pathogenic changes (20).…”

Section: Vol 75 2001 Notesmentioning

confidence: 99%

Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

Ben-Arieh

Zimerman

Smorodinsky

et al. 2001

J Virol

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HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/␤2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses.

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“…To investigate whether the sHZmediated up-regulation of IFN-␥-inducible NO synthesis was simply an effect of HZ iron, B10R M were treated for 1 h with increasing 100 -400 M doses of desferrioxamine (DFX), a commonly used iron chelator (35). Then, IFN-␥ Ϯ sHZ were added and nitrite production was monitored after 24 h. As shown in Fig.…”

Section: The Synergistic Effect Of Shz On Ifn-␥-dependent No Inductiomentioning

confidence: 99%

Hemozoin Increases IFN-γ-Inducible Macrophage Nitric Oxide Generation Through Extracellular Signal-Regulated Kinase- and NF-κB-Dependent Pathways

Jaramillo

Gowda

Radzioch

et al. 2003

The Journal of Immunology

125

118

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NO overproduction has been suggested to contribute to the immunopathology related to malaria infection. Even though a role for some parasite molecules (e.g., GPI) in NO induction has been proposed, the direct contribution of hemozoin (HZ), another parasite metabolite, remains to be established. Therefore, we were interested to determine whether Plasmodium falciparum (Pf) HZ and synthetic HZ, β-hematin, alone or in combination with IFN-γ, were able to induce macrophage (Mφ) NO synthesis. We observed that neither Pf HZ nor synthetic HZ led to NO generation in B10R murine Mφ; however, they significantly increased IFN-γ-mediated inducible NO synthase (iNOS) mRNA and protein expression, and NO production. Next, by investigating the transductional mechanisms involved in this cellular regulation, we established that HZ induces extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase phosphorylation as well as NF-κB binding to the iNOS promoter, and enhances the IFN-γ-dependent activation of both second messengers. Of interest, cell pretreatment with specific inhibitors against either NF-κB or the ERK1/2 pathway blocked the HZ + IFN-γ-inducible NF-κB activity and significantly reduced the HZ-dependent increase on IFN-γ-mediated iNOS and NO induction. Even though selective inhibition of the Janus kinase 2/STAT1α pathway suppressed NO synthesis in response to HZ + IFN-γ, HZ alone did not activate this signaling pathway and did not have an up-regulating effect on the IFN-γ-induced Janus kinase 2/STAT1α phosphorylation and STAT1α binding to the iNOS promoter. In conclusion, our results suggest that HZ exerts a potent synergistic effect on the IFN-γ-inducible NO generation in Mφ via ERK- and NF-κB-dependent pathways.

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Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Mononuclear Blood Cells by the Iron Chelators Deferoxamine, Deferiprone, and Bleomycin

Cited by 95 publications

References 41 publications

Iron-Related Proteins

Iron-Related Proteins

Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

Hemozoin Increases IFN-γ-Inducible Macrophage Nitric Oxide Generation Through Extracellular Signal-Regulated Kinase- and NF-κB-Dependent Pathways

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