Broadly neutralizing antibodies (bNAbs) that inhibit infection by up to 90% of circulating strains of HIV have been described in some HIV-1 infected individuals, and shown to be capable of preventing virus infection in the SHIV/macaque model for HIV infection. Defining features of these bNAbs include extensive somatic hypermutation and high affinity for their cognate antigen. In contrast, the predicted precursors of bNAbs have either very low or undetectable affinity for HIV-1 Env protein. This presents a conundrum, in terms of how to initially stimulate naïve B cells that encode germline ancestors of mature bNAbs. One solution may be to present Env antigen to such cells at a high density on a nanoparticle scaffold, thus overcoming low BCR affinity by increasing antigen avidity. We are therefore conducting experiments to test whether the breadth and quality of the Env-specific B cell repertoire can be enhanced using a nanoparticle-based, multivalent immunogen displaying HIV-1 Env; we are also testing whether this may result in more efficient mobilization of naïve B cells that encode germline ancestors of mature bNabs.

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