How HIV-1 entry mechanism and broadly neutralizing antibodies guide structure-based vaccine design

An HIV-1 vaccine that elicits broadly neutralizing antibodies (bNAbs) remains to be developed. Here, we review how knowledge of bNAbs and HIV-1 entry mechanism is guiding the structure-based design of vaccine immunogens and immunization regimens.

Isolation of bNAbs from HIV-1-infected donors has led to an unprecedented understanding of the sites of vulnerability that these antibodies target on the HIV-1 envelope (Env) as well as of the immunological pathways that these antibody lineages follow to develop broad and potent neutralization. Sites of vulnerability, however, reside in the context of diverse Env conformations required for HIV-1 entry, including a prefusion-closed state, a single-CD4-bound intermediate, a three-CD4-bound intermediate, a prehairpin intermediate and postfusion states, and it is not always clear which structural state optimally presents a particular site of vulnerability in the vaccine context. Furthermore, detailed knowledge of immunological pathways has led to debate among vaccine developers as to how much of the natural antibody-developmental pathway immunogens should mimic, ranging from only the recognized epitope to multiple antigens from the antibody-virus coevolution process.

A plethora of information on bNAbs is guiding HIV-1-vaccine development. We highlight consideration of the appropriate structural context from the HIV-1-entry mechanism and extraordinary progress with replicating template B-cell ontogenies.