For many years only two human monoclonal antibodies (HMAbs) recognizing the CD4 induced (CD4i) epitopes of HIV-1 gp120 existed. Although a number of new CD4i HMAbs have been published recently, we have noted that in most attempts to produce HMAbs using EBV transformation a majority of antibodies produced in culture are lost within a few weeks. To determine what kinds of antibodies are made in these cultures we devised a semiquantitative culture to assess the frequency of B cells capable of producing antibodies and a microcompetition assay to determine what kinds of antibodies were made. Our results show that in three patients started on HAART during acute infection the most frequently produced antibodies binding to gp120 were directed against the CD4i epitopes. Our observations suggest that CD4i epitopes are much more immunogenic than had been previously appreciated. It is possible that envelope glycoproteins shed from virions and perhaps complexed with CD4 are responsible for eliciting these antibodies. The preservation of well regulated immune responses in these patients, together with repeated exposure to viral antigens (i.e. env), may explain the presence of larger than usual numbers of env-specific B cells that could be detected in EBV transformed cultures.