Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies

After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1 vaccine is challenging, including the extraordinary genetic diversity of HIV-1 and its complex mechanisms of immune evasion. HIV-1 envelope glycoproteins are poorly recognized by the immune system, which means that potent broadly neutralizing antibodies (bnAbs) are only infrequently induced in the setting of HIV-1 infection or through vaccination. Thus, the biology of HIV-1–host interactions necessitates novel strategies for vaccine development to be designed to activate and expand rare bnAb-producing B cell lineages and to select for the acquisition of critical improbable bnAb mutations. Here we discuss strategies for the induction of potent and broad HIV-1 bnAbs and outline the steps that may be necessary for ultimate success. There are many reasons why the development of a potent and durable vaccine to HIV-1 is exceptionally challenging, including the large genetic diversity of the virus and its complex mechanisms of immune evasion. In this Review, Haynes et al. discuss strategies for the induction of potent broadly neutralizing antibodies for HIV-1 and the steps that may be necessary for ultimate success.