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(GIST OF SCIENCE REPORTER) Modelling HIV fusion

[March-2021]

An interdisciplinary team of researchers at the Indian Institute of Science (IISc) has used robust computer simulations to understand how HIV – the virus that causes AIDS – fuses with the host cell membrane.
It was published in the Journal of Chemical Information and Modeling, the study focuses on a process called gp41–mediated membrane fusion.
Gp41, a core component of the HIV envelope protein (Env), is essential for the viral membrane to fuse with the cell membrane of the host’s immune cell, called T cell. This step is critical for HIV to invade and subsequently replicate within the host cell.
Although a lot is known about the molecular details of viral entry, the optimal stoichiometry – the balance of components – required for infection has remained uncertain.
The HIV envelope protein assembles into a three-part structure such that each unit comprises one gp41 protein. At the time of fusion, gp41 appears to fold into a six-helix bundle structure, which is thought to be necessary for membrane fusion. The team first built computational models of HIV and host cell membranes and then simulated the fusion process.

Starting with no gp41 on the HIV membrane as the baseline, the authors incrementally added gp41 units to their simulation. On doing so, they found that at least three gp41 units act cooperatively and are necessary for fusion.
In another first, the team built models of HIV and host membranes with lipid compositions nearly identical to biological membranes. Using different membrane models, the authors showed that only the membranes with such identical lipid composition fused successfully, while the rest did not, indicating that the lipid composition of the membranes is critical for fusion.
The researchers also analysed the nature of lipid transfer during fusion and found that the trio of gp41 units drives changes to the structure and arrangement of lipids at the site of fusion. Finally, using mathematical calculations, the team found that the presence of gp41 reduces the energy required for fusion by about four-fold, thereby making this process more favourable.