Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity

Division of Biology, California Institute of Technology, Pasadena, California, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 03/2010; 17(5):608-13. DOI: 10.1038/nsmb.1796
Source: PubMed


Strategies to combat HIV-1 require structural knowledge of envelope proteins from viruses in HIV-1 clade C, the most rapidly spreading subtype in the world. We present a crystal structure containing a clade C gp120 envelope. The structure, a complex between gp120, the host receptor CD4 and the CD4-induced antibody 21c, reveals that the 21c epitope involves contacts with gp120, a nonself antigen, and with CD4, an autoantigen. Binding studies using wild-type and mutant CD4 show that 21c Fab binds CD4 in the absence of gp120, and that binding of 21c to clade C and HIV-2 gp120s requires the crystallographically observed 21c-CD4 interaction. Additional binding data suggest a role for the gp120 V1V2 loop in creating a high-affinity, but slow-forming, epitope for 21c after CD4 binds. These results contribute to a molecular understanding of CD4-induced antibodies and provide the first visualization to our knowledge of a potentially autoreactive antibody Fab complexed with both self and nonself antigens.

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Article: Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity

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    • "Secreted gp120 was captured on Ni 2+ -NTA resin (GE Healthcare) and further purified using Superdex 200 16/60 size exclusion chromatography. Soluble CD4 domains 1 and 2 (sCD4) and sCD4 K75T were produced as described previously by Diskin et al. (2010). Briefly, the pACgp67b vector encoding 63-His-tagged sCD4 or sCD4 K75T (residues 1–186 of mature CD4) was used to make infectious baculovirus particles using BaculoGold (BD Bioscience ). "
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    Cell Reports 04/2014; 7(3). DOI:10.1016/j.celrep.2014.04.001 · 8.36 Impact Factor
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    • "According to a recent study, when the V1V2 domain and gp41 contacts are removed, the native monomer gp120 core adopts a conformation similar to a CD4 bound monomer conformation [61]. In Table 1, we have listed several properties of these reactive peptide regions based on known X-ray structures of liganded gp120 [48-53]. Trends in properties, such as secondary structure and solvent exposure, are consistent among different peptide within a reactive region. "
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    PLoS ONE 09/2013; 8(9):e75665. DOI:10.1371/journal.pone.0075665 · 3.23 Impact Factor
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    • "The anti-influenza antibody 2D1 contains a three-codon insertion in a HV4-like region of FR3 which, while not directly involved in antigen recognition, causes a critical conformational shift in nearby CDRs that is required for antigen recognition (Krause et al., 2011). A unique example of HV4-like contribution to antigen recognition is the anti-HIV antibody 21c (Diskin et al., 2010). 21c binds to the HIV co-receptor binding pocket, which is only exposed following binding of CD4, the primary host receptor. "
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