title: Role of hexokinase-1 in the survival of HIV-1-infected macrophages.
abstract: Viruses have developed various strategies to protect infected cells from apoptosis. HIV-1 infected macrophages are long-lived and considered reservoirs for HIV-1. One significant deciding factor between cell survival and cell death is glucose metabolism. We hypothesized that HIV-1 protects infected macrophages from apoptosis in part by modulating the host glycolytic pathway specifically by regulating hexokinase-1 (HK-1) an enzyme that converts glucose to glucose-6-phosphate. Therefore, we analyzed the regulation of HK-1 in HIV-1 infected PBMCs, and in a chronically HIV-1 infected monocyte-like cell line, U1. Our results demonstrate that HIV-1 induces a robust increase in HK-1 expression. Surprisingly, hexokinase enzymatic activity was significantly inhibited in HIV-1 infected PBMCs and in PMA differentiated U1 cells. Interestingly, we observed increased levels of mitochondria-bound HK-1 in PMA induced U1 cells and in the HIV-1 accessory protein, viral protein R (Vpr) transduced U937 cell derived macrophages. Dissociation of HK-1 from mitochondria in U1 cells using a pharmacological agent, clotrimazole (CTZ) induced mitochondrial membrane depolarization and caspase-3/7 mediated apoptosis. Dissociation of HK-1 from mitochondria in Vpr transduced U937 also activated caspase-3/7 activity. These observations indicate that HK-1 plays a non-metabolic role in HIV-1 infected macrophages by binding to mitochondria thereby maintaining mitochondrial integrity. These results suggest that targeting the interaction of HK-1 with the mitochondria to induce apoptosis in persistently infected macrophages may prove beneficial in purging the macrophage HIV reservoir.
authors.affiliation: a Department of Biology ; College of Science and Technology ; Temple University ; Philadelphia , PA USA.
authors.forename: Satarupa
authors.initials: S
authors.lastname: Sen
authors.forename: Rafal
authors.initials: R
authors.lastname: Kaminiski
authors.forename: Satish
authors.initials: S
authors.lastname: Deshmane
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
authors.forename: Shohreh
authors.initials: S
authors.lastname: Amini
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Datta
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D015658:HIV Infections / Q000201:enzymology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006593:Hexokinase / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000201:enzymology* / Q000821:virology; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000201:enzymology; D009000:Monocytes / Q000201:enzymology; D021381:Protein Transport
chemical_list: C472074:HK1 protein, human; D006593:Hexokinase
keywords: COXIV, Cytochrome c oxidase subunit IV; CTZ, Clotrimazole; G-6-P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; HIV-1; HK-1, Hexokinase-1; M-CSF, macrophage colony-stimulating factor; OMM, outer mitochondrial membrane; VDAC, voltage-dependent anion channel; Vpr, viral protein R; apoptosis, glucose metabolism; cART, combination antiretroviral therapy; hexokinase; macrophage; mitochondria