Elicitation of broadly neutralizing antibodies (bNABs) against the constantly mutating HIV is at the heart of meeting the global health challenge of HIV vaccine development. Broadly neutralizing antibodies is a consistent protective immune correlate in HIV long-term non-progressors as well as in passive immunotherapy studies. Inability to elicit bNABs is the core reason underlining the repeated failures in HIV vaccine research and development. Rare monoclonal bNABs against HIV have only been generated from screening HIV patients. The fundamental significance of generating and studying more monoclonal bNABs against HIV is underlined by its capability of defining critical epitopes for antigen designs aimed at development of a serum-neutralizing HIV vaccine. In this regard, traditional antigen preparations have failed. There is an obvious need to clearly advocate the concept, and systematic study, of more sophisticated ‘designer immunogens’ or ‘designer antigens’ (DAGS) which carry those bNAB epitopes. This project is an investigation of a novel and systematic approach to produce (not screen for) potential bNABs against HIV. The HIV cell-to-cell infection procedure is an extremely efficient and currently irreplaceable method for large scale preparation of the HIV pre-fusion DAGs. Using this model with co-culture mix of H3B virus donor and HUT78 virus acceptor cells, we have established the concept and the experimental system for producing formaldehyde-fixed HIV DAGs which carry frame-frozen pre-fusion intermediates. These pre-fusion intermediates are structures on the cell surface after viral attachment and receptor engagement but before fully functional viral entry. Using defined HIV pre-fusion DAGs we have produced monoclonal antibodies that are specific to novel epitopes on HIV pre-fusion intermediates. This is a paradigm shift from the current mainstream approach of screening for elite patients’ bNABs.