Membrane raft microdomains mediate lateral assemblies required for HIV-1 infection.
HIV-1 infection triggers lateral membrane diffusion following interaction of the viral envelope with cell surface receptors. We show that these membrane changes are necessary for infection, as initial gp120-CD4 engagement leads to redistribution and clustering of membrane microdomains, enabling subsequent interaction of this complex with HIV-1 co-receptors. Disruption of cell membrane rafts by cholesterol depletion before viral exposure inhibits entry by both X4 and R5 strains of HIV-1, although viral replication in infected cells is unaffected by this treatment. This inhibitory effect is fully reversed by cholesterol replenishment of the cell membrane. These results indicate a general mechanism for HIV-1 envelope glycoprotein-mediated fusion by reorganization of membrane microdomains in the target cell, and offer new strategies for preventing HIV-1 infection.
Mañes
S
S
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain. smanes@cnb.uam.es
del Real
G
G
Lacalle
R A
RA
Lucas
P
P
Gómez-Moutón
C
C
Sánchez-Palomino
S
S
Delgado
R
R
Alcamí
J
J
Mira
E
E
Martínez-A
C
C
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000378:metabolism / Q000494:pharmacology; D017930:Genes, Reporter; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology*; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D047392:beta-Cyclodextrins
D015704:CD4 Antigens; D003505:Cyclodextrins; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol