Passive immunization as tool to identify protective HIV-1 Env epitopes

The HIV-1/AIDS epidemic continues to escalate, and a protective vaccine remains elusive. The first vaccine candidate, gp120, did not induce broadly neutralizing antibodies (nAbs) against primary HIV-1 isolates and was ineffective in phase III clinical trials. Attention then focused on generating cytotoxic lymphocyte (CTL)-based vaccines. Interest in anti-HIV-1 nAbs was renewed when passive immunization with human neutralizing monoclonal antibodies (nmAbs) completely protected macaques after intravenous and mucosal challenges with simian-human immunodeficiency viruses (SHIVs) encoding HIV-1 env. These nmAbs targeted conserved, functionally important epitopes on gp120 and gp41. Protection in primate/SHIV models was observed when nmAbs were used singly (nmAbs 2G12, b12) and in various combination regimens (nmAbs b12, F105, 2G12, 2F5, 4E10). Passive immunization, a well-established tool to determine the correlates of protective immunity, thus identified protective epitopes. The three-dimensional structures of some of the latter were recently elucidated, generating important information to design nAb-response-base immunogens. However, several of the protective nmAbs were found to exhibit autoreactivity, raising the possibility that B-cell responses against the cognate epitopes may be difficult to induce by active immunization. It will be important to explore whether broad neutralization can be dissociated from autoreactivity. Future experiments will reveal whether other conserved HIV-1 Env epitopes exist, antibodies against which will be broadly neutralizing in vitro, protective as passive immunization in SHIV-challenged macaques, but lacking autoreactivity. Since all protective epitopes identified to date are located on HIV-1 clade B Env, future studies should include analysis of nmAbs against non-clade B strains.