title: Three-dimensional structures of soluble CD4-bound states of trimeric simian immunodeficiency virus envelope glycoproteins determined by using cryo-electron tomography.
abstract: The trimeric envelope glycoprotein (Env) spikes displayed on the surfaces of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) virions are composed of three heterodimers of the viral glycoproteins gp120 and gp41. Although binding of gp120 to cell surface CD4 and a chemokine receptor is known to elicit conformational changes in gp120 and gp41, changes in quaternary structure of the trimer have only recently been elucidated. For the HIV-1 BaL isolate, CD4 attachment results in a striking rearrangement of the trimer from a "closed" to an "open" conformation. The effect of CD4 on SIV trimers, however, has not been described. Using cryo-electron tomography, we have now determined molecular architectures of the soluble CD4 (sCD4)-bound states of SIV Env trimers for three different strains (SIVmneE11S, SIVmac239, and SIV CP-MAC). In marked contrast to HIV-1 BaL, SIVmneE11S and SIVmac239 Env showed only minor conformational changes following sCD4 binding. In SIV CP-MAC, where trimeric Env displays a constitutively "open" conformation similar to that seen for HIV-1 BaL Env in the sCD4-complexed state, we show that there are no significant further changes in conformation upon the binding of either sCD4 or 7D3 antibody. The density maps also show that 7D3 and 17b antibodies target epitopes on gp120 that are on opposites sides of the coreceptor binding site. These results provide new insights into the structural diversity of SIV Env and show that there are strain-dependent variations in the orientation of sCD4 bound to trimeric SIV Env.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Tommi A
authors.initials: TA
authors.lastname: White
authors.forename: Alberto
authors.initials: A
authors.lastname: Bartesaghi
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Borgnia
authors.forename: M Jason V
authors.initials: MJ
authors.lastname: de la Cruz
authors.forename: Rachna
authors.initials: R
authors.lastname: Nandwani
authors.forename: James A
authors.initials: JA
authors.lastname: Hoxie
authors.forename: Julian W
authors.initials: JW
authors.lastname: Bess
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Jacqueline L S
authors.initials: JL
authors.lastname: Milne
authors.forename: Sriram
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015704:CD4 Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D055032:Electron Microscope Tomography; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus; C076613:recombinant soluble CD4