The human immunodeficiency virus (HIV) continues to pose a significant global health burden. A critical step in its life cycle is the fusion of the viral membrane with that of a host cell—a process mediated by the gp41 fusion peptide, a component of the viral envelope protein complex. This peptide acts as a molecular lever, disrupting the host membrane to initiate viral entry. In our recent study, we present a detailed biophysical characterization of this fusion event, offering new insights into the molecular strategy used by HIV.
The accompanying cover image of the August 5 issue of Biophysical Journal, rendered by using the 3D modeling software Blender, visually represents the key findings of our study. It illustrates the gp41 fusion peptide (depicted as a helical structure) inserting into the lipid bilayer of the host cell. During this interaction, water molecules (shown as bluish gray spheres in the center of the cover) are expelled from the membrane surface, while the surrounding lipids are driven into a more tightly packed arrangement. This combination of membrane dehydration and increased lipid ordering forms the central mechanism by which gp41 promotes membrane fusion. Our conclusions are based on complementary biophysical techniques. Neutron reflectivity enabled precise quantification of hydration changes at the membrane interface, while fluorescence lifetime imaging microscopy provided a measure of lipid packing density. Together, these methods allowed us to reconstruct a detailed molecular view of the fusion process.
Importantly, we observed that gp41 exhibits enhanced activity in membranes characterized by lateral heterogeneity and disorder—conditions that mimic the nanodomains found in biological membranes. Interestingly, the introduction of negatively charged lipids attenuated the peptide’s ability to induce dehydration and packing, despite its continued penetration into the membrane. This suggests a nuanced dependence of fusion activity on membrane composition and charge properties. These findings have broader implications for antiviral strategies. Whereas current HIV therapies primarily target post-entry stages of the viral life cycle, our work points toward the possibility of interfering with the initial fusion event. Agents that stabilize membrane hydration or prevent excessive lipid packing may serve as viable candidates to inhibit viral entry.
Furthermore, the fusion mechanism uncovered here may not be unique to HIV. Several other enveloped viruses, including influenza and severe acute respiratory syndrome coronavirus 2, use similar fusion peptides for host entry. As such, the principles identified in this study could inform the development of broad-spectrum antiviral interventions with potential relevance beyond HIV. You can find more information on our work at https://physics.iisc.ac.in/~basu/.
— Shovon Swarnakar, Anurag Chaudhury, Maximilian W. A. Skoda, Hirak Chakraborty, and Jaydeep K. Basu