Dual germline-targeting strategy to elicit diverse anti-CD4-BS bNAbs against HIV-1

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Project Summary/Abstract: An important obstacle in the development of a vaccine against HIV-1 is the inability of the viral glycoprotein (Env) to engage the naïve precursor B-cell receptor (BCR) forms of known HIV-1 broadly neutralizing antibodies (bNAbs). bNAbs bind conserved epitopes on Env and, as a result, can prevent infection by diverse HIV-1 strains. The VRC01-class bNAbs are derived from the VH1-2 heavy chain (HC) gene paired with light chains (LC) expressing only 5 aa-long CDR3 domains, target the CD4- binding site (CD4-BS) epitope of Env, and two phase 3 clinical trials indicated that they can reduce HIV-1 acquisition. To elicit VRC01-class bNAbs through vaccination, germline-targeting (GT) immunogens have been developed that bind the germline, unmutated bNAb BCRs. One such GT immunogen is 426c.Mod.Core.C4b, which engages B cells with glVRC01 BCRs in both preclinical models and in participants in a phase 1 clinical trial (HVTN301). In our preclinical studies leveraging transgenic mice that express the human glVRC01 HC and LC genes, we use a prime-boost strategy with 426c.Mod.Core.C4b and two heterologous Env-derived proteins to then guide the maturation of these glVRC01 BCRs to more broadly neutralizing forms. Current results from HVTN301 indicate that, in addition to VRC01-class antibodies, 426c.Mod.Core.C4b also activates a different class of anti-CD4-BS bNAbs, a VH1-46-derived class. Therefore, the studies proposed here aim to develop a prime-boost GT immunization strategy to optimally guide the maturation of VH1-46 bNAb precursors into broadly neutralizing forms. Additionally, because we observed competition, in vitro, between the VH1-2-class and the VH1-46-derived antibodies elicited by 426c.Mod.Core.C4b in HVTN301, we intend to evaluate the dynamics of lineage competition in vivo, by using an adoptive transfer model where both glVRC01- and glVH1-46-expressing B cells are transferred into WT mice (which do not express such BCRs) before immunizing them with 426c.Mod.Core.C4b, to track the activation and maturation of both bNAb-producing precursor lineage B cells. The proposed studies will provide important new information on the development of a prime-boost immunization strategy that may lead to the elicitation of more than one CD4-BS bnAb lineage in clinical settings, thus minimizing viral escape.