Dihydrosphingomyelin impairs HIV-1 infection by rigidifying liquid-ordered membrane domains.
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 (l(d)) and the liquid-ordered (l(o)); the putative presence of gel domains (s(o)) is not usually taken into account. We show that in phospholipid:sphingolipid:cholesterol mixtures, in which sphingomyelin (SM) promoted fluid l(o) 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.
Vieira
Catarina R
CR
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, E-28049 Madrid, Spain.
Munoz-Olaya
Jose M
JM
Sot
Jesús
J
Jiménez-Baranda
Sonia
S
Izquierdo-Useros
Nuria
N
Abad
Jose Luis
JL
Apellániz
Beatriz
B
Delgado
Rafael
R
Martinez-Picado
Javier
J
Alonso
Alicia
A
Casas
Josefina
J
Nieva
José L
JL
Fabriás
Gemma
G
Mañes
Santos
S
Goñi
Félix M
FM
D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D008561:Membrane Fusion / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D013109:Sphingomyelins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism
C091181:4,5-dihydrosphingomyelin; D015700:HIV Envelope Protein gp41; D013109:Sphingomyelins; D053835:Unilamellar Liposomes; C514787:gp41 protein, Human immunodeficiency virus 1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase