CaltechTHESIS
  A Caltech Library Service

Structure and Dynamics of HIV-1 Env Trimer

Citation

Wang, Haoqing (2019) Structure and Dynamics of HIV-1 Env Trimer. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/65VD-VM42. https://resolver.caltech.edu/CaltechTHESIS:02272019-142326751

Abstract

The human immunodeficiency virus-1 (HIV-1) infects CD4+ helper T cells by fusing its lipid membrane to the host cell plasma membrane. HIV-1 Envelope (Env) glycoprotein, a trimer of gp120-gp41 heterodimers, is the fusion machinery that mediates viral and host cell membrane fusion, which is initiated by interaction between the host cell receptor CD4 and viral glycoprotein gp120. Receptor binding induces conformational changes in the Env trimer such that coreceptor CCR5/CXCR4 can bind to gp120 and trigger subsequent membrane fusion steps. Previous cryo-electron tomography (cryoET) and spectroscopy studies have shown that CD4 binding induces changes in Env trimer from the closed, prefusion conformation to an open, CD4-bound conformation. However, the CD4-bound Env trimer is dynamic and flexible such that structural biology study of CD4-bound Env trimer is difficult.

As the sole glycoprotein located on HIV-1 viral surface, Env trimer is the only target for neutralizing antibodies. Since HIV-1 mutates rapidly, most neutralizing antibodies are strain-specific. However, a small percent of HIV-1 infected patients can develop broadly neutralizing antibodies (bNAbs) that neutralize a wide spectrum of viruses. In 2011, our collaborator isolated a bNAb called 8ANC195. To understand how 8ANC195 recognizes Env trimer and prevents infection, we used a combination of structural biology and biochemistry tools. Interestingly, we found that 8ANC195 can recognize Env trimer in both its prefusion and CD4-bound conformations by targeting an epitope at gp120-gp41 interface. Furthermore, 8ANC195 stabilizes the Env-CD4 complex, allowing us to investigate the conformational changes induced by CD4 in atomic resolution. By solving and comparing single-particle cryo-EM structures of Env trimer in complex with CD4 and/or antibodies, we found that: 1) CD4 binding induces coreceptor binding site exposure through a β-sheet rearrangements in each gp120 monomer. Several key residues allosterically regulate this coreceptor binding site exposure. 2) CD4 binding induces Env trimer opening together with gp41 conformational changes, which represents an intermediate between prefusion gp41 and postfusion gp41. 3) Env trimer opening is necessary but not sufficient for coreceptor binding site exposure, while CD4 binding induces both, some antibodies can open Env trimer without exposing the coreceptor binding site. These conclusions further illuminate how Env trimer mediates membrane fusion and inform potential strategies blocking viral entry.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:HIV-1 envelope; viral membrane fusion; cryoelectron microscopy
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biochemistry and Molecular Biophysics
Minor Option:Computational Science and Engineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Bjorkman, Pamela J.
Thesis Committee:
  • Jensen, Grant J. (chair)
  • Clemons, William M.
  • Rees, Douglas C.
  • Bjorkman, Pamela J.
Defense Date:14 December 2018
Record Number:CaltechTHESIS:02272019-142326751
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:02272019-142326751
DOI:10.7907/65VD-VM42
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2015.08.035DOIArticle adapted for Ch. 2.
https://doi.org/10.1016/j.chom.2018.09.003DOIArticle adapted for Ch. 3.
https://doi.org/10.7554/eLife.27389DOIArticle adapted for Ch. 4.
ORCID:
AuthorORCID
Wang, Haoqing0000-0003-0277-3018
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11413
Collection:CaltechTHESIS
Deposited By: Haoqing Wang
Deposited On:18 Mar 2019 17:21
Last Modified:04 Oct 2019 00:24

Thesis Files

[img]
Preview
PDF - Final Version
See Usage Policy.

28MB

Repository Staff Only: item control page