title: Increased metallothionein gene expression, zinc, and zinc-dependent resistance to apoptosis in circulating monocytes during HIV viremia.
abstract: 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.
authors.affiliation: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104-4268, USA.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Raymond
authors.forename: Bethsebah
authors.initials: B
authors.lastname: Gekonge
authors.forename: Malavika S
authors.initials: MS
authors.lastname: Giri
authors.forename: Aidan
authors.initials: A
authors.lastname: Hancock
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Papasavvas
authors.forename: Jihed
authors.initials: J
authors.lastname: Chehimi
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossevkov
authors.forename: Calen
authors.initials: C
authors.lastname: Nicols
authors.forename: Malik
authors.initials: M
authors.lastname: Yousef
authors.forename: Karam
authors.initials: K
authors.lastname: Mounzer
authors.forename: Jane
authors.initials: J
authors.lastname: Shull
authors.forename: Jay
authors.initials: J
authors.lastname: Kostman
authors.forename: Louise
authors.initials: L
authors.lastname: Showe
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D015658:HIV Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D014766:Viremia / Q000150:complications / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D053222:Fas Ligand Protein; C530151:SLC39A8 protein, human; D008668:Metallothionein; D015032:Zinc