An aptamer that neutralizes R5 strains of HIV-1 binds to core residues of gp120 in the CCR5 binding site.
We have previously isolated nucleic acid ligands (aptamers) that bind the surface envelope glycoprotein, gp120, of HIV-1, and neutralize infection of diverse sub-types of virus. Our earlier studies have identified the overall structure of one of these aptamers, B40, and have indicated that it binds to gp120 in a manner that competes with that of the HIV-1 coreceptor, CCR5, and select "CD4i" antibodies with epitopes overlapping this region. Here, we sought to map the B40 binding site on gp120 more precisely by analysing its interaction with a panel of alanine substitution mutants of gp120. Furthermore, we tested our hypothesis concerning the structure of the 40 nucleotide functional core of the aptamer by the solid-phase synthesis of truncated and chemically modified derivatives. The results confirm our structural predictions and demonstrate that aptamer B40 neutralizes a diverse range of HIV-1 isolates as a result of binding to relatively conserved residues on gp120 at the heart of the CCR5-binding site. These structural insights may provide the basis for the development of potential anti-viral agents with high specificity and robustness.
Cohen
Carla
C
Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK. ccohen@bccrc.ca
Forzan
Mario
M
Sproat
Brian
B
Pantophlet
Ralph
R
McGowan
Ian
I
Burton
Dennis
D
James
William
W
D019380:Anti-HIV Agents / Q000494:pharmacology*; D052157:Aptamers, Nucleotide; D001665:Binding Sites; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D012313:RNA / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism*
D019380:Anti-HIV Agents; D052157:Aptamers, Nucleotide; D015699:HIV Envelope Protein gp120; C502124:RNA aptamer B40; D019713:Receptors, CCR5; D012313:RNA
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