Dihydrosphingomyelin Impairs HIV-1 Infection by Rigidifying Liquid-Ordered Membrane Domains

SummaryThe lateral organization of lipids in cell membranes is thought to regulate numerous cell processes. Most studies focus on the coexistence of two fluid phases, the liquid crystalline (ld) and the liquid-ordered (lo); the putative presence of gel domains (so) is not usually taken into account. We show that in phospholipid:sphingolipid:cholesterol mixtures, in which sphingomyelin (SM) promoted fluid lo domains, dihydrosphingomyelin (DHSM) tended to form rigid domains. Genetic and pharmacological blockade of the dihydroceramide desaturase (Des1), which replaced SM with DHSM in cultured cells, inhibited cell infection by replication-competent and -deficient HIV-1. Increased DHSM levels gave rise to more rigid membranes, resistant to the insertion of the gp41 fusion peptide, thus inhibiting viral-cell membrane fusion. These results clarify the function of dihydrosphingolipids in biological membranes and identify Des1 as a potential target in HIV-1 infection.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (235 K)Download as PowerPoint slideHighlights► We show that dihydrosphingolipids form solid-ordered microdomains in model membranes ► Des1 inhibition increases dihydrosphingolipid levels in the membrane of living cells ► Chemical and genetic blockade of Des1 activity inhibits infection by HIV-1 ► Dihydrosphingolipid-enriched membranes are less prone to HIV-1 gp41-mediated fusion