3D Structure of HIV Envelope Protein

3D structure of HIV envelope protein sheds light on first contact between virus and cell

The lab of Dr. R Holland Cheng focuses on the structural biology of viruses via cryoelectron microscopy (cryoEM), and its scope of interest includes HIV. Recently, we published a paper in PNAS outlining the structure of an immunogen based on the HIV envelope protein, which was rationally designed as a vaccine candidate. Using the single particle reconstruction technique, we derived a three-dimensional density map of the gp140 immunogen. The paper outlines the changes that the trimeric, fan-shaped complex gp140 undergoes as a result of ligand binding, including exposure of crucial conserved binding sites and promotion of host and viral membrane fusion. By comparing the gp140 complex in its native, unliganded state with gp140 bound to its receptor, key differences in quaternary structure were analyzed. The primary observations gleaned from our comparison were that the interaction between each trimeric arm and the central stalk was weakened after binding to CD4, that the trimer undergoes some flattening, and that the subunits in each “fan blade” rotate to expose a previously cryptic binding site. These findings allowed us to devise a model for membrane fusion whereby the weakening of interaction between subunits facilitates refolding of the central stalk protein, allowing for juxtaposition and subsequent fusion of the viral and host cell membranes. Such a model provides the rationale behind the steps following this crucial first contact between virus and cell. Increased understanding of the membrane fusion events will facilitate virologists looking for ways to thwart them, as well as enhance rational vaccine design of an immunogen capable of inducing potently and broadly neutralizing antibodies.