HIV-1 neutralizing antibodies: understanding nature's pathways

The development of an effective vaccine has been hindered by the enormous diversity of human immunodeficiency virus-1 (HIV-1) and its ability to escape a myriad of host immune responses. In addition, conserved vulnerable regions on the HIV-1 envelope glycoprotein are often poorly immunogenic and elicit broadly neutralizing antibody responses (BNAbs) in a minority of HIV-1-infected individuals and only after several years of infection. All of the known BNAbs demonstrate high levels of somatic mutations and often display other unusual traits, such as a long heavy chain complementarity determining region 3 (CDRH3) and autoreactivity that can be limited by host tolerance controls. Nonetheless, the demonstration that HIV-1-infected individuals can make potent BNAbs is encouraging, and recent progress in isolating such antibodies and mapping their immune pathways of development is providing new strategies for vaccination.