Increased metallothionein gene expression, zinc, and zinc-dependent resistance to apoptosis in circulating monocytes during HIV viremia
| Autor: | Calen Nicols, Jay Kostman, Jane Shull, Louise C. Showe, Bethsebah Gekonge, Emmanouil Papasavvas, Andrew V. Kossevkov, Andrea D. Raymond, Malik Yousef, Aidan Hancock, Malavika S. Giri, Karam Mounzer, Jihed Chehimi, Luis J. Montaner |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Fas Ligand Protein Immunology Intracellular Space Viremia Apoptosis HIV Infections Biology Virus Replication Monocytes Immune system Cell Movement Gene expression medicine Immunology and Allergy Metallothionein Humans Cation Transport Proteins Regulation of gene expression Monocyte virus diseases Translational and Clinical Immunology Cell Biology medicine.disease Molecular biology Zinc medicine.anatomical_structure Gene Expression Regulation HIV-1 Intracellular |
| Zdroj: | Journal of leukocyte biology. 88(3) |
| ISSN: | 1938-3673 |
| Popis: | Differential expression of metallothionein genes and high intracellular zinc promote monocyte survival during HIV infection. Circulating monocytes exhibit an apoptotic resistance phenotype during HIV viremia in association with increased MT expression. MTs are known to play an important role in zinc metabolism and immune function. We now show, in a cross-sectional study using peripheral monocytes, that expression of MT1 isoforms E, G, H, and X is increased significantly in circulating monocyte cells from HIV+ subjects during chronic viremic episodes as compared with uninfected subjects. This increase in expression is also observed during acute viremia following interruption of suppressive ART. Circulating monocytes from HIV+ donors were also found to have elevated zinc importer gene Zip8 expression in conjunction with elevated intracellular zinc levels in contrast to CD4+T-lymphocytes. In vitro HIV-1 infection studies with elutriated MDM confirm a direct relation between HIV-1 infection and increased MDM MT1 (isoform G) gene expression and increased intracellular zinc levels. A direct link between elevated zinc levels and apoptosis resistance was established using a cell-permeable zinc chelator TPEN, which reversed apoptosis resistance effectively in monocytes from HIV-infected to levels comparable with uninfected controls. Taken together, increases in MT gene expression and intracellular zinc levels may contribute directly to maintenance of an immune-activated monocyte by mediating an increased resistance to apoptosis during active HIV-1 viremia. |
| Databáze: | OpenAIRE |
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