Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice

Abstract

VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype.

Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques

“…We observed that clonal lineages were shared among many tissues ( Figures 5C, 6, and 7) but only ~45% of these lineages had members found in peripheral blood (Table 1). Given recent work aimed at stimulating germline precursors of broadly neutralizing antibodies and quantifying those responses (29)(30)(31), data from the present study suggest that sampling of blood alone may not be able to detect all vaccine-elicited responses.…”

Molecular Architecture of the Cleavage-Dependent Mannose Patch on a Soluble HIV-1 Envelope Glycoprotein Trimer

“…Inducing VRC01 class bNAbs is the goal of several Env vaccine programs based on targeting specific precursors of these antibodies in the human germ line repertoire followed by a boosting regimen intended to drive the maturation of any initially induced precursors. These programs use a variety of Env proteins, including those based on gp120 outer domains, gp120 monomers, or nonnative gp140s (74)(75)(76). The glycoform compositions of these immunogens will need to be determined experimentally, but some sites (including N276, when present) may be processed more highly than those on native trimers, based on what we have seen with the BG505 gp120 monomers and uncleaved pseudotrimers.…”

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

“…Enormous advances are being made in isolating bnAbs against HIV from patients (10-15), understanding the evolutionary pathways that lead to bnAbs in individuals (23)(24)(25)(26)(27)(28), and developing immunogens to activate the germline B cells that can mature into bnAbs (17)(18)(19)(20)(21)35 (3,6,8,20,22,34). Our past work leading to this conclusion considered variant Ags separated by relatively large mutational distances.…”

“…A few structural elements on the HIV envelope are conserved across the viral population and present immunogenic epitopes for BCRs (39). Germline B cells that can target such epitopes have a chance to evolve into bnAbs, and recent studies have shown how designed immunogens can activate such cells (17)(18)(19)(20)(21). We study how these germline B cells might evolve on immunization with different types of mixtures of variant Ags.…”

“…Plasma B cells secrete Abs, which are modified forms of the BCR. There is a growing consensus that guiding this Darwinian evolutionary process toward the production of bnAbs will require immunization with an Ag that activates the correct germline B cells (17)(18)(19)(20)(21) followed by multiple variant Ags that share a set of conserved residues and mimic the HIV viral spike (3,6,8,20,22).…”