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

Dihydrosphingomyelin Impairs HIV-1 Infection by Rigidifying Liquid-Ordered Membrane Domains
Catarina R. Vieira, Jose M. Munoz-Olaya, Jesús Sot, Sonia Jiménez-Baranda, Nuria Izquierdo-Useros, Jose Luis Abad, Beatriz Apellániz, Rafael Delgado, Javier Martinez-Picado, Alicia Alonso, Josefina Casas, José L. Nieva, Gemma Fabriás, Santos Mañes, Félix M. GoñiSee

Affiliations: Rollover Authors and Affiliations Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, E-28049 Madrid, Spain Department of Biomedicinal Chemistry, Institute of Advanced Chemistry of Catalonia (IQAC)/CSIC, Jordi Girona 18, 08034 Barcelona, Spain Unidad de Biofísica (Centro Mixto CSIC-UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, P.O. Box 644, E-48080 Bilbao, Spain irsiCaixa Foundation, Hospital Universitari Germans Trias i Pujol, E-08916 Badalona, Spain Hospital Universitario 12 de Octubre, Avenida. Andalucía s/n, E-28049 Madrid, Spain ICREA, Barcelona, Spain Corresponding author These authors contributed equally to this work These authors contributed equally to the design and direction of this work

Graphical Abstract
Highlights
•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

Summary
The 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.

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Chemistry and Biology - Dihydrosphingomyelin Impairs HIV-1 Infection by Rigidifying Liquid-Ordered Membrane Domains
Chemistry & Biology, Volume 17, Issue 7, 766-775, 30 July 2010; doi:10.1016/j.chembiol.2010.05.023
http://www.cell.com/chemistry-biology/fulltext/S1074-5521(10)00214-0

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