Increased metallothionein gene expression, zinc, and zinc-dependent resistance to apoptosis in circulating monocytes during HIV viremia

Journal of Leukocyte Biology

Malik Yousef³  Andrea D. Raymond³  Karam Mounzer²  Emmanouil Papasavvas³  Jay Kostman¹  Bethsebah Gekonge³  Malavika S. Giri³  Aidan Hancock³  Calen Nicols³  Louise Showe³  Jane Shull²  Andrew V. Kossevkov³  Jihed Chehimi³  Luis J. Montaner³ 

[1] Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; and Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; andPhiladelphia Field Initiating Group for HIV-1 Trials, Philadelphia, Pennsylvania, USA; Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, Pennsylvania, USA; Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, Pennsylvania, USA;The Wistar Institute, Philadelphia, Pennsylvania, USA; The Wistar Institute, Philadelphia, Pennsylvania, USA; The Wistar Institute, Philadelphia, Pennsylvania, USA;

关键词: AIDS;    macrophages;    MT1;   

DOI  :  10.1189/jlb.0110051

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown