A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, United States
Science (Impact Factor: 31.48). 07/1998; 280(5371):1949-53. DOI: 10.1126/science.280.5371.1949
Source: PubMed

ABSTRACT The entry of primate immunodeficiency viruses into target cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors, CD4 and members of the chemokine receptor family. The gp120 third variable (V3) loop has been implicated in chemokine receptor binding, but the use of the CCR5 chemokine receptor by diverse primate immunodeficiency viruses suggests the involvement of an additional, conserved gp120 element. Through the use of gp120 mutants, a highly conserved gp120 structure was shown to be critical for CCR5 binding. This structure is located adjacent to the V3 loop and contains neutralization epitopes induced by CD4 binding. This conserved element may be a useful target for pharmacologic or prophylactic intervention in human immunodeficiency virus (HIV) infections.

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    • "Exclusion of amino acid positions 11 and 25 decreased the accuracy by approximately 5%, with position 11 contributing the majority of the lost information [248] Overall, these results suggest that all amino acids within the V3 region contribute to co-receptor usage selection. In addition, further studies involving HIV-1 envelope mutagenesis have indicated that amino acid residues outside the V3 loop region could influence the structure of gp120 induced by CD4 binding, which is critical for co-receptor binding and viral tropism [248] [249]. "
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    • "This additional inhibitory function of V2 mAbs was not measured in the neutralization assay used in the study because the TZM-bl target cells do not express α4β7 integrin. Thus, in the TZM-bl cell assay, the anti-V2 mAbs mediate neutralization by affecting the co-receptor binding site which is formed by the stem of the V1V2, V3 and the bridging sheet upon virus binding to the CD4 receptor (Kwong et al., 1998; Rizzuto et al., 1998; Wu et al., 1996). Evidently, this mechanism of neutralization, which has a post-binding character exhibited after the virus binds to cellular CD4, is responsible for the neutralizing activity of anti-V2 mAbs in the TZM-bl cell assay. "
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    • "H77.39 and J6.36) mapping to HVR1 or contiguous regions, we did not observe this effect for weakly neutralizing MAbs (H77.31 and J6.27) that localize to the CD81 binding region. The failure to observe enhanced inhibitory activity by E2-specific MAbs that interfere with CD81 binding may reflect a requirement for more significant structural shifts for complete epitope exposure, analogous to the those required to reveal the CCR5 binding epitope on HIV gp120 (Kwong et al., 1998; Rizzuto et al., 1998). Indeed, previous studies have demonstrated that anti-CD81 antibodies inhibit infection at a postattachment step, indicating that CD81 is not completely engaged by the virus directly after attachment (Bertaux and Dragic, 2006; Haberstroh et al., 2008; Sabo et al., 2011). "
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