Isolated, antigenic polypeptides including a pre-hairpin intermediate conformation of gp41 and vectors encoding such polypeptides are provided. Antibodies that bind to a pre-hairpin intermediate conformation of gp41 and methods of making antibodies a that bind to pre-hairpin intermediate conformation of gp41 are also provided. Vaccines against a pre-hairpin Fd intermediate conformation of gp41, as well as methods of treating subjects infected with HIV, preventing HIV infection, and inhibiting HIV-mediated activities are also provided. Methods of screening compounds that bind to an isolated, pre-hairpin intermediate conformation of gp41 are further provided.
