Although early work on developing an HIV-1 vaccine investigated the role of neutralizing antibodies, most of the recent work has focused on vaccines that stimulate cytotoxic T cells. Now, as reported in the Proceedings of the National Academy of Sciences, Maxime Moulard and colleagues have isolated a neutralizing antibody that recognizes an epitope on a complex between HIV-1 envelope glycoprotein 120, CD4 and CC-chemokine receptor 5 (gp120–CD4–CCR5). This antibody is broadly cross-reactive with HIV-1 isolates from various clades, which has implications for vaccine development.

HIV-1 enters host cells by forming a complex between gp120, the CD4 receptor and a chemokine co-receptor, which might be CCR5 or CXC-chemokine receptor 4 (CXCR4), depending on the HIV-1 isolate. Binding of gp120 causes conformational changes in the HIV-1 envelope protein and initiates the cell-fusion process, but the precise mechanism of HIV-1 entry is not fully understood. Working on the theory that intermediate conformations of the envelope protein might contain epitopes that are conserved between different HIV-1 isolates — which could be effective vaccine targets— Moulard and colleagues used a phage-display approach to identify neutralizing antibodies specific for these epitopes.

Using purified gp120–CD4–CCR5 complexes as the selecting antigen, the group identified a human antibody Fab (fragment of antigen binding), X5, from a phage-display library that was generated from a seropositive donor. X5 bound to envelope proteins from primary isolates of various clades with high affinity (nM range). The binding of X5 to gp120 was significantly enhanced by CD4, which indicates that the gp120 epitope is exposed to a greater extent after gp120–CD4 interaction. X5 was able to inhibit the infection of blood cells by different HIV-1 primary isolates with a potency that was comparable to that of a previously identified neutralizing antibody.

So, the identification of X5 implies that conserved conformational epitopes can be recognized by potent, broadly neutralizing antibodies, and this might be an important area for further study.