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Natural and engineered antibodies against HIV

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The humoral arm of the immune system exerts continual selective pressure on HIV replication in the infected person. We have described a conserved epitope within the gp120 V3 loop that is masked in the native Env trimer on CCR5-restricted (R5) HIV-1 virions, but fully exposed on CXCR4-using (X4, R5X4) virions. The ability of a monoclonal antibody against this epitope to selectively neutralize CXCR4-using but not CCR5-restricted primary isolates raises the question of whether in vivo neutralizing antibody selection pressure in the acutely infected person plays a major role in the selective transmission of R5 viruses.

We are exploiting antibodies to engineer novel bifunctional proteins against HIV infection. One agent, designated sCD4-17b, is based on the sequential receptor binding mechanism of gp120: first to CD4, then to coreceptor. The sCD4 moiety of the chimeric protein binds and induces the conformational change required to expose/create the highly conserved "bridging sheet" involved in coreceptor binding and containing the 17b epitope. The potent neutralizing activity of sCD4-17b against diverse HIV-1 primary isolates suggests its potential utility as a topical microbicide to protect against HIV-1 sexual transmission. [1, 2].

References

  1. 1.

    Lusso P, Earl PL, Sironi F, Santoro F, Ripamonti C, Scarlatti G, Longhi R, Berger EA, Burastero SE: Cryptic nature of a conserved, CD4-inducible V3 loop neutralization epitope in the native envelope glycoprotein oligomer of CCR5-restricted, but not CXCR4-using, primary human immunodeficiency virus type 1 strains. J Virol. 2005, 79: 6957-6968. 10.1128/JVI.79.11.6957-6968.2005.

  2. 2.

    Dey B, Del Castillo CS, Berger EA: Neutralization of human immunodeficiency virus type 1 by sCD4-17b, a single-chain chimeric protein, based on sequential interaction of gp120 with CD4 and coreceptor. J Virol. 2003, 77: 2859-2865. 10.1128/JVI.77.5.2859-2865.2003.

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Correspondence to Edward A Berger.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Infected Person
  • Primary Isolate
  • Potent Neutralize
  • Bifunctional Protein
  • Coreceptor Binding