Vaccine elicitation of HIV broadly neutralizing antibodies from engineered B cells

Deli Huang,Jenny Tuyet Tran,James E Voss,Mary Tenuta,William R Schief ,Dennis R Burton,Torben Schiffner,Mariia V Guryleva,Ben Murrell,Wenjuan Li,Alicia González-Martín ,Alex Olson,Roberta P Fuller,Tanya R Blane,David Nemazee,Elise Landais,Karen Saye,Lauren Couvrette,Thomas Vollbrecht,Justin R Abadejos

doi:10.1038/s41467-020-19650-8

Abstract

HIV broadly neutralizing antibodies (bnAbs) can suppress viremia and protect against HIV infection. However, their elicitation is made difficult by low frequencies of appropriate precursor B cell receptors and the complex maturation pathways required to generate bnAbs from these precursors. Antibody genes can be engineered into B cells for expression as both a functional antigen receptor on cell surfaces and as secreted antibody. Here, we show that HIV bnAb-engineered primary mouse B cells can be adoptively transferred and vaccinated in immunocompetent mice resulting in the expansion of durable bnAb memory and long-lived plasma cells. Somatic hypermutation after immunization indicates that engineered cells have the capacity to respond to an evolving pathogen. These results encourage further exploration of engineered B cell vaccines as a strategy for durable elicitation of HIV bnAbs to protect against infection and as a contributor to a functional HIV cure.

Highlights

HIV broadly neutralizing antibodies can suppress viremia and protect against HIV infection
Genetic limitations imposed by the human repertoire of B cell antigen receptors (BCRs) from which such antibodies must arise, has significantly impeded these efforts
Characterization of a variety of bnAbs discovered in chronically infected patients shows that they generally derive from B cell precursors with uncommon antigen receptor features, such as long third heavy chain (HC) complementarity determining regions (CDRH3s), and require extensive somatic hypermutation to facilitate broad neutralization[3,4]

Summary

Results

Modified primary B cells express the HIV VRC01 bnAb as antigen receptor. Wild-type (WT) C57BL/6J (or B6) mice are a useful model in which to explore vaccine elicitation of HIV bnAbs from engineered cells because of similarities between the mouse and human humoral immune systems, and because such bnAbs cannot be elicited from the natural repertoire[11,12,13]. After targeting using either the H or H + κ engineering strategies, 40,000 VRC01 BCR-expressing cells were engrafted per animal into WT recipient mice This corresponds to ~3 in 100,000 B cells present after parking for 14 days in vivo (Supplementary Fig. 3b). Donor DNA encoding (1) a HC V-gene promoter, (2) the VRC01 κ chain (with mouse constant gene and P2A peptide), (3) the VRC01 HC variable (VDJ) region and donor splice site is inserted at a CRISPR-Cas[9] cut site in JH4 for expression as a functional antigen receptor using endogenous downstream HC constant genes. Engineered cells in mice from this group were expanded 20–70-fold during the prime and boost (Fig. 3g) and VRC01-expressing memory (GT8++, KO11−, donor+) cells became mostly CD73+, implying their entry into GCs after vaccination, unlike GT8− donor cells, which remained CD73− after LPS treatment (Fig. 3h, i). Repertoires mostly conserved the original VRC01 amino acid sequence, an abundance of variants with coding changes were present, including some highly mutated lineages emerging in the memory compartment

69.2 GT8-AF647

Methods

Code availability