Bioinformatics and Statistics

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PROJECT SUMMARY Vaccines that can induce broadly neutralizing antibodies (bNAbs) will be needed to protect against the global diversity of HIV-1 strains, however they do not currently exist (1,2). Vaccine induction of bNAbs will require two critical steps. First, priming of the appropriate bNAb precursors that, due to unusual features, are rare in the naïve human B-cell repertoire (3–5). Second, such precursors will need to be guided to acquire critical somatic hypermutations that confer heterologous neutralization potency and breadth (6). While it is clear that bNAbs evolve in natural HIV-1 infections through years of Env-antibody (Ab) coevolution, it is not clear how to trans- late these findings to design immunogens that can reproducibly prime and mature bNAbs across multiple hosts (1,5,7). In our last HIVRAD project, we developed a novel rhesus macaque (RM) SHIV infection model that re- capitulated several key features of Env-bNAb coevolution (8,9). We also showed that prior vaccination and in- fection with SHIVs bearing particular germline-targeting Envs could accelerate bNAb development. Thus, our rhesus model system thus provides a unique setting where reproducible induction of bNAbs in (S)HIV infec- tions can be studied. In this renewal, we will leverage this system to develop a vaccination and SHIV infection strategy that will lead to development of V3 glycan bNAbs in an accelerated and reproducible manner across multiple rhesus hosts. Our scientific premise is that a better understanding of the common Env-Ab coevolu- tionary patterns leading to V3 glycan bNAb development will allow design of immunogens that can prime and mature multiple V3 glycan bNAb lineages. Our Bioinformatics and Statistics Core (Core C) will provide bioin- formatic and statistical modeling analyses to facilitate these overall HIVRAD goals. We will analyze Env evolu- tion in SHIV-infected RMs from Project 1 by applying our novel computational pipeline to longitudinal se- quence data generated by Core B. We will identify the similarities and differences between the neutralization profiles of newly identified rhesus V3 glycan bNAbs (Project 1) and previously known V3 glycan bNAbs (Aim 2). Using the above two studies, we will iteratively design immunogens that are capable of engaging precur- sors of multiple V3 glycan bNAb lineages and of maturing them towards neutralization breadth in collaboration with Core B and Project 3 (Aim 3). Finally, we will provide statistical modeling of in vivo vaccine efficacy (Pro- ject 1) and other complex biological problems across all Projects.