Role of hexokinase-1 in the Survival of HIV-1-infected Macrophages

Cell Cycle. 2015;14(7):980-9. doi: 10.1080/15384101.2015.1006971.

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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cell Survival
  • HIV Infections / enzymology*
  • HIV Infections / virology
  • HIV-1 / physiology*
  • Hexokinase / physiology*
  • Humans
  • Macrophages / enzymology*
  • Macrophages / virology
  • Membrane Potential, Mitochondrial
  • Mitochondria / enzymology
  • Monocytes / enzymology
  • Protein Transport

Substances

  • HK1 protein, human
  • Hexokinase