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Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and have selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from approximately 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses. Despite over two decades of research, a protective vaccine against HIV-1 remains elusive. It is widely accepted that such a vaccine will require the elicitation of both T-cell mediated immunity and a broadly neutralizing antibody response (1-3). All of the known bNAbs provide protection in the best available primate models (4-9) and therefore are considered to be the types of antibodies that should be elicited by a vaccine. Unfortunately, these antibodies tend to display limited breadth and potency against non-clade B viruses, which make up the majority of infections outside North America and Europe, and they recognize epitopes on the virus that have so far failed to elicit broadly neutralizing responses when incorporated into a diverse range of immunogens We have screened serum from approximately 1,800 HIV-1 infected donors from Thailand, Australia, the UK, the United States, and several sub-Saharan African countries for neutralization activity and identified donors who exhibit broad and potent neutralizing serum activit