HIV gp41-Mediated Membrane Fusion Occurs at Edges of Cholesterol-Rich Lipid Domains

Lipid rafts in plasma membranes have emerged as possible platforms for entry of HIV and other viruses into cells. However, how lipid phase heterogeneity contributes to viral entry is little known due to the fine-grained and still poorly understood complexity of biological membranes. We used model systems mimicking HIV envelopes and T-cell membranes and showed that raft-like (L(o) phase) lipid domains are necessary and sufficient for efficient membrane targeting and fusion. Interestingly, membrane binding and fusion was low in homogeneous L(d) and L(o) phase membranes, indicating that lipid phase heterogeneity is essential. The HIV fusion peptide preferentially targeted to L(o)/L(d) boundary regions and promoted full fusion at the interface between ordered and disordered lipids. L(d) phase vesicles proceeded only to hemifusion. Thus, we propose that the edges, but not the areas of raft-like ordered lipid domains are vital for HIV entry and membrane fusion.