Marek Mössl

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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
Ulrich Schubert

Synthetic Mimicry of the HIV-1 gp120 epitope for the anti-HIV-1 antibody mAb b12

Synthetic molecules capable of structurally and/or functionally mimicking protein binding sites are excellent tools for the exploration and understanding of protein structure and function. Furthermore, such mimetic molecules are promising candidates for a range of biomedical applications, in particular the modulation of protein function through controlled interference with the underlying molecular interactions.
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. So far, only very few antibodies have been found that are able to neutralize a broad range of HIV-1 isolates in vitro, as well as to protect against infection in vivo. The epitope of one of the best of these broadly neutralizing antibodies, mAb b12 (b12E), 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 and the b12E are therefore promising candidates as entry inhibitors, as well as immunogens for the elicitation of virus-neutralizing antibodies.
Based on the resolved crystal structure of gp120 complexed with mAb b12, the primary contact residues of gp120 for its interaction with mAb b12 could be identified. The goal of this project is to design and generate peptides which present fragments of gp120 that comprise these contact residues, constituting its epitope for mAb b12 (b12E). The affinities to mAb b12 of these epitope mimetics, as well as the specificity of this interaction, will be evaluated in competitive binding assays, as well as by surface plasmon resonance measurements. The interaction of the mimetic peptides with mAb b12 will be dissected at the level of individual amino acid positions using substitution analogs (chemical mutation).
Furthermore, in collaboration with Prof. Dr. Ulrich Schubert (Virology Institute of the FAU), promising peptides, as well as respective anti-peptide antibodies, will be evaluated regarding their ability to prevent infection of CD4+ cells with HIV-1.

Figure: Structural detail of mAb b12 in complex with an HIV-1 gp120 core. Section of the gp120 (right) – mAb b12 (left) complex structure[1]. The heavy chain complementary-determining regions are shown in green (CDR H1), yellow (CDR H2) and red CDR H3. The gp120 fragments that constitute the mAb b12 epitope are shown in blue and magenta. The primary contact residues are shown as stick model. For mAb b12 these make up about 40 percent of the total contact surface with gp120. [1] Zhou et al. (2007). Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732-737.

 

Publications

 

Presentations

October 2011 First International SFB 796 Conference: Mechanisms of viral host cell manipulations: from plants to humans, Bamberg, Germany
Cross Reactivity of Synthetic Peptides Mimicking the Epitope for the Anti-HIV-1 Antibody mAb b12  and the CD4-Binding Site of gp120
Poster
     
July 2011 3rd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Synthetic mimicry of the HIV-1 gp 120 epitope for the antibody mAb b12
Talk
     
March 2011 10. Deutsches Peptidsymposium, Berlin, Germany
Cross Reactivity of Synthetic Peptides Mimicking the Epitope for the Anti-HIV-1 Antibody mAb b12 and the CD4-Binding Site of gp120
Poster
     
September 2010 2nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Synthetic mimicry of the HIV-1 gp 120 epitope for the antibody mAb b12
Talk
     
September 2009 First Annual Retreat, Erlangen School of Molecular Communication, Schloss Atzelsberg, Atzelsberg, Germany
Synthetic mimicry of the HIV-1 gp 120 epitope for the antibody mAb b12
Talk