Arne Berthelmann

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A5 Exploration of the structural basis for the functional mimicry of the CD4 binding site of the HIV-1 gp120: Implications for virus entry inhibition and the induction of broadly neutalizing antibodies

Principal investigator
Jutta Eichler

Mentor
Yves Muller

PhD exam: 15.07.2014

Exploration of the structural basis for the functional mimicry of the CD4 binding site of HIV-1 gp120

The human immunodeficiency virus (HIV-1), the agent of the aquired immune deficiency syndrome AIDS, represents one of the most important threats to humans. More than 33 million people worldwide were infected with HIV-1 in 2007, and an estimated 2 million people died from AIDS.
Despite enormous efforts in basic and clinical research, HIV-1 vaccine development is greatly hampered by the difficulty in eliciting a virus-neutralizing antibody response. Innovative strategies in immunogen design are needed to address the neutralizing antibody issue, which remains one of the most difficult problems to be solved in the development of a successful HIV-1 vaccine. The epitope of one of the best neutralizing antibodies, mAb b12, overlaps the binding site of the viral envelope glycoprotein gp120 for its cellular receptor CD4 (CD4bs), which represents a conserved region in this otherwise highly variable protein. Synthetic mimetics of the CD4bs (CD4bs-M) are therefore promising candidates as entry inhibitors as well as immunogens for the elicitation of virus-neutralizing antibodies.
Starting from synthetic CD4bs mimetic peptides of the first generation (CD4bs-M, Figure), the aim of this project is the structural analysis of this mimetic peptide in complex with CD4. This information is expected to provide insight into structural similarities and differences in the interactions of gp120 and CD4bsM with CD4, which will in turn guide the design of improved, specific CD4bs mimetics as entry inhibitors, as well as immunogen candidates for the elicitation of broadly neutralizing anti-HIV-1 antibodies.
Furthermore, we will address the question whether trivalent presentation of the CD4bs mimetic peptides improves their affinities to CD4. Based on a 3D model of trimeric HIV-1 env spikes, we will generate trimers of CD4bs mimetic peptides by attaching them to three sites of molecular scaffolds.

Figure: Section of the crystal structure of core gp120 with CD4, which shows the interface of gp120 and CD4. (b): Synthetic mimetic peptide of CD4bs (CD4bs-M) of HIV-1 gp120. (c): Competition of CD4bs-M with gp120 for binding to mAb b12 and CD4.

 

Publications

 

Presentations

July 2012 4th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Trivalent presentation of synthetic HIV-1 gp120 derived peptides
Talk
     
October 2011 First International SFB 796 Conference: Mechanisms of viral host cell manipulations: from plants to humans, Bamberg, Germany
Trivalent Presentation of a Synthetic Mimetic of the CD4 Binding Site of HIV-1 gp120
Poster
     
July 2011 3rd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Structural optimization of a mimetic of the CD4 binding site of HIV-1 gp120
Talk
     
July 2011 3nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Trivalent Presentation of a Synthetic Mimetic of the CD4 Binding Site of HIV-1 gp120
Poster
     
March 2011 13. JCF Frühjahrssymposium, Erlangen, Germany
Trivalent Presentation of a Synthetic Mimetic of the CD4 Binding Site of HIV-1 gp120
Poster
     
March 2011 Deutsches Peptidsymposium 2011, Berlin, Germany
Trivalent Presentation of a Synthetic Mimetic of the CD4 Binding Site of HIV-1 gb120
Talk, Poster
     
September 2010 2nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Structural optimization of a mimetic of the CD4 binding site of HIV-1 gp120
Talk
     
August 2010 3. EuCheMS, Nuremberg, Germany
Trivalent presentation of a synthetic mimetic of the CD4 binding site of HIV-1 gp120
Poster
     
September 2009 First Annual Retreat, Erlangen School of Molecular Communication, Schloss Atzelsberg, Atzelsberg, Germany
Structural optimization of a mimetic of the CD4 binding site of HIV-1 gp120
Talk

 

Awards

Cooperation Award together with Martin Grießl and Kristin Kaßler
3rd Annual Retreat of the Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany, July 2011
"Strukturelle Aufklärung der Bindung zwischen dem potyviralen Hüllprotein PVY-CP und seinem zellulären Interaktionspartner aus N. tabacum" .