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

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.

Energetics of stalk intermediates in membrane fusion are controlled by lipid composition

“…The ratio of 2-3 deduced from the above numbers is well compatible with recent observations that 1-3 SNARE complexes are sufficient to achieve membrane fusion (66,74). In line with the present results, the inhibition of fusion observed after depletion of cholesterol, both in SNARE-mediated (75) and viral fusion (76,77), as well an increase of the docking efficiency in SNARE-mediated vesicle fusion upon higher PE content (78), may result from the effects of these lipids on the hydration barrier W hyd .…”

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

“…A subsequent report showed that CXCR4 in PBLs and T cell lines was excluded from rafts irrespective of HIV binding (Kozak et al, 1999). More recently it was shown that in T cell lines, both CCR5 and CXCR4, were raft associated and required cholesterol for optimal signaling Taub, 2002a, 2002b) and productive HIV infection (Liao et al, 2001;Popik et al, 2002). Some of the above inconsistencies stem from the use of different cell types, and the various assays for raft association were not designed to analyze the cell surface receptors exclusively.…”

Lipidomics of host–pathogen interactions

“…Cholesterol in target membrane is required for fusion and infection [101,102] Cholesterol is required for entry of mycobacteria into macrophages [103] Cholesterol (host) controls T. gondii entry [38]. Lipid rafts of red blood cell membranes are involved in formation of the parasitophorous vacuolar membrane around P. falciparum [36] ST N ER …”