A lack of neutralizing antibodies distinguishes HIV-1 from most other viral pathogens and is responsible to a large degree for the ability of HIV-1 to maintain a persistent infection. A few monoclonal antibodies have been isolated that are broadly neutralizing. We have used X-ray crystallography to investigate the epitopes of broadly neutralizing antibodies and their mechanisms of neutralization. In particular, we have examined CD4-binding-site directed antibodies like VRC01, V1/V2-directed antibodies like PG9 and PG16, and membrane-proximal-binding antibodies like 2F5 and 10E8. The VRC01 antibody is particularly attractive as it neutralizes over 90% of circulating HIV-1 isolates and appears to be elicited in high titer in 5-10% of HIV-1 infected individuals;however its uncommon development make its elicitation problematic. The V1/V2-directed and V3-glycan antibodies are also attractive, as some estimate that these are the most commonly elicited broadly neutralizing responses. Antibodies against the membrane-proximal region of HIV-1 are also attractive, as this region is highly conserved and recognition does not involve N-linked glycan.

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