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 hig hly specialized membrane microdomains known as lipid rafts. These microdoma ins are characterized by a distinct lipid composition that includes high co ncentrations of cholesterol, sphingolipids, and glycolipids. Since choleste rol is known to play a key role in the entry of some other viruses, our obs ervation 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 suscep tible cells. We have used 2-OH-propyl-beta -cyclodextrin (beta -cyclodextri n) to deplete cellular cholesterol and disperse lipid rafts. Our results sh ow that removal of cellular cholesterol rendered primary cells and cell lin es highly resistant to HIV-1-mediated syncytium formation and to infection by both CXCR4- and CCR5-specific viruses. beta -Cyclodextrin treatment of c ells partially reduced HIV-1 binding, while rendering chemokine receptors h ighly sensitive to antibody-mediated internalization. There was no effect o n CD4 expression. All of the above described effects were readily reversed by incubating cholesterol-depleted cells with low concentrations of cholest erol-loaded beta -cyclodextrin to restore cholesterol levels. Cholesterol d epletion made cells resistant to SDF-1-induced binding to ICAM-1 through LF A-1. Since LFA-1 contributes significantly to cell binding by HIV-1, this l atter effect may have contributed to the observed reduction in HIV-1 bindin g to cells after treatment with beta -cyclodextrin. Our results indicate th at cholesterol may be critical to the HIV-1 coreceptor function of chemokin e receptors and is required for infection of cells by HIV-1.