Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Science (Impact Factor: 31.48). 11/2009; 326(5956):1123-7. DOI: 10.1126/science.1175868
Source: PubMed

ABSTRACT The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.

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Available from: Dennis R Burton, Jul 17, 2015
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    • "It was suggested that the poor antibody response to the conserved CD4BD OD epitopes was due to the superior intrinsic immunogenicity of gp120 variable domain epitopes (Boudet et al., 1992; Montefiori et al., 1993) and conformational flexibility of gp120 (Kwong et al., 2002). Conformational differences between the CD4BD OD epitopes expressed by monomer gp120 and oligomeric gp120 on the viral surfaces have also been invoked to explain the poor CD4BD OD antibody response induced by the former immunogen (Chen et al., 2009). Extensive and sophisticated projects were designed to develop analogs of gp120 that overcome these weaknesses, but no immunogen capable of inducing broadly neutralizing antibodies has emerged. "
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    Frontiers in Immunology 12/2012; 3:383. DOI:10.3389/fimmu.2012.00383
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    • "Such approaches have, however, been unsuccessful for a number of reasons that probably include the following: (1) Until very recently, only a few bnMAbs were available so that, for instance, all attempts to design immunogens based on the CD4bs were guided by the sole anti-CD4bs bnMAb, b12. The remarkable discoveries of many more potent anti- CD4bs bnMAbs in the last 2 years may renew opportunities in this area (Corti et al., 2010; Falkowska et al., 2012; Scheid et al., 2011; Wu et al., 2010; Wu et al., 2011), although there are still concerns that unusually precise directional targeting to the CD4bs epitope may be required (Chen et al., 2009). (2) Targeting the glycan epitope recognized by the bnMAb 2G12 presents problems in terms of the special domain-exchanged configuration of this antibody (Calarese et al., 2003), which was thought necessary for recognition of the glycan shield that surrounds gp120. "
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    Cell host & microbe 10/2012; 12(4):396-407. DOI:10.1016/j.chom.2012.09.008 · 12.19 Impact Factor
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    • "The best model, with 81.5% sequence identity and 89.5% sequence similarity, had the highest verify score of 56.01. [24]. Studies have shown that the CD4-specific DARPin 57.2 efficiently binds to CD4+ T cells, DCs, and monocytes in vivo but has no effect on SHIV plasma levels after a single intravenous injection into SHIV-infected rhesus macaques. "
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