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Developing Novel HIV-1 Vaccine Immunogens

With >36 million people infected and almost 2 million new infections in 2016, the need for a prophylactic HIV-1 vaccine is as urgent as ever. Approximately 20-30% of HIV-1 infected individuals generate antibodies capable of neutralizing diverse heterologous viral strains (broadly neutralizing antibodies or bNAbs). Because they protect from experimental infection, it is thought that bNAbs will be an important part of an HIV-1 vaccine. Yet immunization of humans with recombinant Env leads to the production of antibodies with very narrow breadth of neutralization which fail to block infection of diverse circulating viral isolates. The isolation of monoclonal bNAbs from HIV-1+ individuals has provided valuable information on how bNAbs develop during infection, and on the epitope specificities on the HIV-1 Envelope protein (Env) that an effective vaccine should aim to elicit.

One of the first critical steps in an effective antibody response is the recognition of a foreign antigen by a membrane anchored B cell receptor (BCR) on the surface of a naïve B cell. Naive BCRs arise through the random recombination of germline-encoded immunoglobulin genes during B cell development. Antigen recognition triggers a cascade of events that lead to B cell clonal expansion and somatic hypermutation; critical processes that stochastically diversify the BCR repertoire by introducing mutations into the BCR-encoding DNA. Expanded pools of diverse B cell clones compete for antigen and T cell help in a Darwinian process that ultimately selects for B cells with higher affinity receptors which can be secreted as soluble molecules (antibodies).  As a result of these processes many of the bNAbs are highly mutated and highly divergent from their ancestral BCRs from which they are derived. As a consequence of bNAb precursors fail to bind most recombinant HIV-1 Envs (such as those that would be used in HIV-1 vaccines).  Thus, one potential reason for the failure of HIV-1 vaccines to elicit bNAbs is that the Env immunogens tested failed to engage bNAb precursor B cells, and thus failed to start the process of bnAb production. As an alternative to using HIV-1 Env as a vaccine immunogen, we are pursuing a novel vaccine strategy where we generate anti-idiotypic antibodies: antibodies raised in a non-human animal model that bind with high affinity and specificity to bNAb precursors. Importantly, because these immunogens are not Env-derived, they should not stimulate non-neutralizing B cell lineages which are readily elicited by conventional Env-vaccines. We are currently generating, optimizing and testing these immunogens in various humanized mouse models.

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