Knowledge of the molecular structure of trimeric Env on intact viruses and delineating the mechanisms of cell-cell transmission are central to the design of effective immunogens and therapeutic agents to combat HIV/AIDS. We have continued to make significant progress towards these goals over the last year. Major advances we have made over the last year include: (i) discovery of variations in the type of virological synapses involved in mediating HIV transmission between different types of cell-cell contacts including T-cell-T-cell and T-cell-dendritic cell synapses;(ii) molecular structures of trimeric HIV-1 and SIV envelope glycoproteins from a large number of viral strains and from soluble immunogens;(iii) demonstration that soluble gp140 immunogens can display the same ligand-induced changes in conformation that are seen with native envelope glycoproteins;(iv) the unexpected finding that binding of trimeric envelope glycoproteins to a co-receptor mimic alone induces the same conformational changes as binding to CD4 and (v) structural evidence, at sub-nanometer resolution, of a novel, activated intermediate state of HIV where highly conserved, interior components of the viral spike are exposed, providing a template for the design of immunogens aimed at eliciting antibodies that could block HIV entry.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010825-06
Application #
8552847
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$905,109
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Tran, Erin E H; Podolsky, Kira A; Bartesaghi, Alberto et al. (2016) Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate. MBio 7:e00257
Tran, Erin E H; Nelson, Elizabeth A; Bonagiri, Pranay et al. (2016) Mapping of Ebolavirus Neutralization by Monoclonal Antibodies in the ZMapp Cocktail Using Cryo-Electron Tomography and Studies of Cellular Entry. J Virol 90:7618-27
Earl, Lesley A; Subramaniam, Sriram (2016) Cryo-EM of viruses and vaccine design. Proc Natl Acad Sci U S A 113:8903-5
Moulaei, Tinoush; Alexandre, Kabamba B; Shenoy, Shilpa R et al. (2015) Griffithsin tandemers: flexible and potent lectin inhibitors of the human immunodeficiency virus. Retrovirology 12:6
Tran, Erin E H; Simmons, James A; Bartesaghi, Alberto et al. (2014) Spatial localization of the Ebola virus glycoprotein mucin-like domain determined by cryo-electron tomography. J Virol 88:10958-62
Do, Thao; Murphy, Gavin; Earl, Lesley A et al. (2014) Three-dimensional imaging of HIV-1 virological synapses reveals membrane architectures involved in virus transmission. J Virol 88:10327-39
Narayan, Kedar; Danielson, Cindy M; Lagarec, Ken et al. (2014) Multi-resolution correlative focused ion beam scanning electron microscopy: applications to cell biology. J Struct Biol 185:278-84
Merk, Alan; Subramaniam, Sriram (2013) HIV-1 envelope glycoprotein structure. Curr Opin Struct Biol 23:268-76
Harris, Audray K; Bartesaghi, Alberto; Milne, Jacqueline L S et al. (2013) HIV-1 envelope glycoprotein trimers display open quaternary conformation when bound to the gp41 membrane-proximal external-region-directed broadly neutralizing antibody Z13e1. J Virol 87:7191-6
Meyerson, Joel R; Tran, Erin E H; Kuybeda, Oleg et al. (2013) Molecular structures of trimeric HIV-1 Env in complex with small antibody derivatives. Proc Natl Acad Sci U S A 110:513-8

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