Increased metallothionein gene expression, zinc, and zinc-dependent resistance to apoptosis in circulating monocytes during HIV viremia.
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.
Raymond
Andrea D
AD
The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104-4268, USA.
Gekonge
Bethsebah
B
Giri
Malavika S
MS
Hancock
Aidan
A
Papasavvas
Emmanouil
E
Chehimi
Jihed
J
Kossenkov
Andrew V
AV
Kossevkov
Andrew V
AV
Nicols
Calen
C
Yousef
Malik
M
Mounzer
Karam
K
Shull
Jane
J
Kostman
Jay
J
Showe
Louise
L
Montaner
Luis J
LJ
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*
D027682:Cation Transport Proteins; D053222:Fas Ligand Protein; C530151:SLC39A8 protein, human; D008668:Metallothionein; D015032:Zinc