Lipid rafts and HIV pathogenesis: host membrane cholesterol is required for infection by HIV type 1.
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.
Liao
Z
Z
Immunochemistry Laboratory, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cimakasky
L M
LM
Hampton
R
R
Nguyen
D H
DH
Hildreth
J E
JE
D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D047392:beta-Cyclodextrins; D002784:Cholesterol; C031215:betadex