Lipid Rafts and HIV Pathogenesis: Host Membrane Cholesterol Is Required for Infection by HIV Type 1

AIDS Res Hum Retroviruses. 2001 Jul 20;17(11):1009-19. doi: 10.1089/088922201300343690.

Abstract

In a previous study we showed that budding of HIV-1 particles occurs at highly specialized membrane microdomains known as lipid rafts. These microdomains are characterized by a distinct lipid composition that includes high concentrations of cholesterol, sphingolipids, and glycolipids. Since cholesterol is known to play a key role in the entry of some other viruses, our observation of HIV budding from lipid rafts led us to investigate the role in HIV-1 entry of cholesterol and lipid rafts in the plasma membrane of susceptible cells. We have used 2-OH-propyl-beta-cyclodextrin (beta-cyclodextrin) to deplete cellular cholesterol and disperse lipid rafts. Our results show that removal of cellular cholesterol rendered primary cells and cell lines highly resistant to HIV-1-mediated syncytium formation and to infection by both CXCR4- and CCR5-specific viruses. beta-Cyclodextrin treatment of cells partially reduced HIV-1 binding, while rendering chemokine receptors highly sensitive to antibody-mediated internalization. There was no effect on CD4 expression. All of the above-described effects were readily reversed by incubating cholesterol-depleted cells with low concentrations of cholesterol-loaded beta-cyclodextrin to restore cholesterol levels. Cholesterol depletion made cells resistant to SDF-1-induced binding to ICAM-1 through LFA-1. Since LFA-1 contributes significantly to cell binding by HIV-1, this latter effect may have contributed to the observed reduction in HIV-1 binding to cells after treatment with beta-cyclodextrin. Our results indicate that cholesterol may be critical to the HIV-1 coreceptor function of chemokine receptors and is required for infection of cells by HIV-1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Cholesterol / metabolism*
  • Cyclodextrins / pharmacology
  • HIV Infections / metabolism*
  • HIV-1 / growth & development*
  • Humans
  • Jurkat Cells
  • Membrane Microdomains / chemistry
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism*
  • Protein Binding
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / metabolism
  • Tumor Cells, Cultured
  • beta-Cyclodextrins*

Substances

  • Cyclodextrins
  • Receptors, CCR5
  • Receptors, CXCR4
  • beta-Cyclodextrins
  • Cholesterol
  • betadex