D102 Molecular structures of trimeric HIV-1 and SIV envelope glycoproteins

The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Entry of HIV and SIV into target cells involves structural changes in gp120 that expose the binding site for a cellular seven-transmembrane-helix co-receptor protein followed by conformational changes in the transmembrane glycoprotein gp41. We have shown recently that these changes involve the formation of an activated intermediate in which three gp41 helices are exposed at the center of the trimeric spike. Insertion of the fusogenic portion of the gp41 polypeptide into the target cell membrane ultimately leads to fusion of the viral and target cell membranes, and delivery of the viral core into infected cells. Cryo-electron microscopic analyses of unliganded and antibody-bound trimeric Env on a variety of HIV-1 and SIV strains are beginning to provide information on the structural diversity of Env and the strain-dependent variations in the structural consequences of ligand binding by Env. In parallel with these studies, we are developing and applying novel methods for 3D imaging of whole mammalian cells to visualize cell-cell virus transfer at virological synapses. Together, these studies provide new insights into the molecular architectures of envelope glycoproteins on HIV and SIV, the molecular basis of antibody-mediated virus neutralization and the mechanisms underlying effective cell-to-cell virus transmission.