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Cell Host Microbe. 2017 Jul 12;22(1):99-110.e7. doi: 10.1016/j.chom.2017.06.012.

Fusion Stage of HIV-1 Entry Depends on Virus-Induced Cell Surface Exposure of Phosphatidylserine.

Author information

1
Section on Membrane Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
2
Section on Intercellular Interactions, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
3
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
4
Flow Cytometry Core, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
5
Section on Membrane Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address: chernoml@mail.nih.gov.

Abstract

HIV-1 entry into host cells starts with interactions between the viral envelope glycoprotein (Env) and cellular CD4 receptors and coreceptors. Previous work has suggested that efficient HIV entry also depends on intracellular signaling, but this remains controversial. Here we report that formation of the pre-fusion Env-CD4-coreceptor complexes triggers non-apoptotic cell surface exposure of the membrane lipid phosphatidylserine (PS). HIV-1-induced PS redistribution depends on Ca2+ signaling triggered by Env-coreceptor interactions and involves the lipid scramblase TMEM16F. Externalized PS strongly promotes Env-mediated membrane fusion and HIV-1 infection. Blocking externalized PS or suppressing TMEM16F inhibited Env-mediated fusion. Exogenously added PS promoted fusion, with fusion dependence on PS being especially strong for cells with low surface density of coreceptors. These findings suggest that cell-surface PS acts as an important cofactor that promotes the fusogenic restructuring of pre-fusion complexes and likely focuses the infection on cells conducive to PS signaling.

KEYWORDS:

HIV entry; TMEM16F activity; cell activation; cell signaling; gp120-CD4-coreceptor; hemifusion; lipid scramblase; membrane fusion; phosphatidylserine exposure; viral entry

Comment in

PMID:
28704658
PMCID:
PMC5558241
DOI:
10.1016/j.chom.2017.06.012
[Indexed for MEDLINE]
Free PMC Article

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