Attacking the Co-Receptor Binding Site on gp120
J Sodroski*1, H Choe4, R Wyatt2, C Grundner1, S-H Xiang1, X Yang1, M Venturi2, A Labrijn3, P Poignard3, A Raja1, D Burton3, P Kwong2 and M Farzan5
1Dana-Farber Cancer Inst, Harvard Med Sch, Harvard Sch of Publ Hlth, Boston, MA; 2Vaccine Res Ctr, NIAID, NIH, Bethesda, MD; 3The Scripps Res Inst, La Jolla, CA; 4Children's Hosp, Harvard Med Sch, Boston, MA; 5Partners AIDS Res Ctr, Harvard Med Sch, Boston, MA
Background:During human immunodeficiency virus (HIV-1) entry into target cells, the vial gp120 exterior envelope glycoprotein must sequentially interact with CD4 and one of two chemokine receptors, CCR5 or CXCR4. Because the receptor-binding sites on gp120 are conserved and accessible, they are potentially vulnerable to neutralization by antibodies. The sites on gp120 involved in binding CCR5 and CXCR4 share common, highly conserved elements. One such conserved element is targeted by the CD4-induced (CD4i) antibodies. The chemokine receptor-binding sites are protected from CD4i neutralizing antibodies by conformational flexibility, overlying variable loops, adjacent glycosylation sites, and steric factors. These factors render primary HIV-1 isolates relatively resistant to neutralization by CD4i antibodies. However, Fab or sFv fragments of CD4i antibodies bypass some of these steric blocks and efficiently neutralize many primary HIV-1 isolates. A subset of CD4i antibodies, even as complete antibodies, can neutralize primary HIV-1 isolates. The unique structural features and neutralization mechanism of these antibodies will be discussed. Attempts to identify immunogens that elicit receptor-directed neutralizing antibodies active against primary HIV-1 strains are warranted.