Dataset Information

Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein of human immunodeficiency virus.

ABSTRACT: The human immunodeficiency virus envelope glycoproteins, gp120 and gp41, function in cell entry by binding to CD4 and a chemokine receptor on the cell surface and orchestrating the direct fusion of the viral and target cell membranes. On the virion surface, three gp120 molecules associate noncovalently with the ectodomain of the gp41 trimer to form the envelope oligomer. Although an atomic-level structure of a monomeric gp120 core has been determined, the structure of the oligomer is unknown. Here, the orientation of gp120 in the oligomer is modeled by using quantifiable criteria of carbohydrate exposure, occlusion of conserved residues, and steric considerations with regard to the binding of the neutralizing antibody 17b. Applying similar modeling techniques to influenza virus hemagglutinin suggests a rotational accuracy for the oriented gp120 of better than 10 degrees. The model shows that CD4 binds obliquely, such that multiple CD4 molecules bound to the same oligomer have their membrane-spanning portions separated by at least 190 A. The chemokine receptor, in contrast, binds to a sterically restricted surface close to the trimer axis. Electrostatic analyses reveal a basic region which faces away from the virus, toward the target cell membrane, and is conserved on core gp120. The electrostatic potentials of this region are strongly influenced by the overall charge, but not the precise structure, of the third variable (V3) loop. This dependence on charge and not structure may make electrostatic interactions between this basic region and the cell difficult to target therapeutically and may also provide a means of viral escape from immune system surveillance.

SUBMITTER: Kwong PD

PROVIDER: S-EPMC111674 | biostudies-literature | 2000 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein of human immunodeficiency virus.

Kwong P D PD Wyatt R R Sattentau Q J QJ Sodroski J J Hendrickson W A WA

Journal of virology 20000201 4

The human immunodeficiency virus envelope glycoproteins, gp120 and gp41, function in cell entry by binding to CD4 and a chemokine receptor on the cell surface and orchestrating the direct fusion of the viral and target cell membranes. On the virion surface, three gp120 molecules associate noncovalently with the ectodomain of the gp41 trimer to form the envelope oligomer. Although an atomic-level structure of a monomeric gp120 core has been determined, the structure of the oligomer is unknown. He ...[more]

PMID: 10644369

Similar Datasets

Project description:The HIV-1 envelope glycoprotein, gp120, undergoes multiple molecular interactions and structural rearrangements during the course of host cell attachment and viral entry, which are being increasingly defined at the atomic level using isolated proteins. In comparison, antigenic markers of these dynamic changes are essentially unknown for single HIV-1 particles bound to target cells. Such markers should indicate how neutralizing and/or non-neutralizing antibodies might interdict infection by either blocking infection or sensitizing host cells for elimination by Fc-mediated effector function. Here we address this deficit by imaging fluorescently labeled CCR5-tropic HIV-1 pseudoviruses using confocal and superresolution microscopy to track the exposure of neutralizing and non-neutralizing epitopes as they appear on single HIV-1 particles bound to target cells. Epitope exposure was followed under conditions permissive or non-permissive for viral entry to delimit changes associated with virion binding from those associated with post-attachment events. We find that a previously unexpected array of gp120 epitopes is exposed rapidly upon target cell binding. This array comprises both neutralizing and non-neutralizing epitopes, the latter being hidden on free virions yet capable of serving as potent targets for Fc-mediated effector function. Under non-permissive conditions for viral entry, both neutralizing and non-neutralizing epitope exposures were relatively static over time for the majority of bound virions. Under entry-permissive conditions, epitope exposure patterns changed over time on subsets of virions that exhibited concurrent variations in virion contents. These studies reveal that bound virions are distinguished by a broad array of both neutralizing and non-neutralizing gp120 epitopes that potentially sensitize a freshly engaged target cell for destruction by Fc-mediated effector function and/or for direct neutralization at a post-binding step. The elucidation of these epitope exposure patterns during viral entry will help clarify antibody-mediated inhibition of HIV-1 as it is measured in vitro and in vivo.

Dataset Information

Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein of human immunodeficiency virus.

Publications

Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein of human immunodeficiency virus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets