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Natural and engineered antibodies against HIV
Retrovirology volume 3, Article number: S100 (2006)
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].
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.
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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Berger, E.A. Natural and engineered antibodies against HIV. Retrovirology 3, S100 (2006) doi:10.1186/1742-4690-3-S1-S100
- Infected Person
- Primary Isolate
- Potent Neutralize
- Bifunctional Protein
- Coreceptor Binding