Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen

By Joseph G. Jardine, T. Ota, D. Sok, M. Pauthner, Daniel W. Kulp, Oleksandr Kalyuzhniy, Patrick D. Skog, Therese C. Thinnes, Deepika Bhullar, Bryan S. Briney and 8 more. 2015

409 citations recorded by the source corpus.

Steps in the right direction HIV-1 mutates rapidly, making it difficult to design a vaccine that will protect people against all of the virus' iterations. A potential successful vaccine design might protect by eliciting broadly neutralizing antibodies (bNAbs), which target specific regions on HIV-1's trimeric envelope glycoprotein (Env) (see the Perspective by Mascola). Jardine et al. used mice engineered to express germline-reverted heavy chains of a particular bNAb and immunized them with an Env-based immunogen designed to bind to precursors of that bNAb. Sanders et al. compared rabbits and monkeys immunized with Env trimers that adopt a nativelike conformation. In both cases, immunized animals produced antibodies that shared similarities with bNAbs. Boosting these animals with other immunogens may drive these antibodies to further mutate into the longsought bNAbs. Chen et al. report that retaining the cytoplasmic domain of Env proteins may be important to attract bNAbs. Removing the cytoplasmic domain may distract the immune response and instead generate antibodies that target epitopes on Env that would not lead to protection. Science, this issue p. 139, 10.1126/science.aac4223, p. 156; see also p. 191 A rationally designed HIV-1 envelope protein antigen helps to initiate the production of broadly neutralizing antibodies in mice. [Also see Perspective by Mascola] A major goal of HIV-1 vaccine research is the design of immunogens capable of inducing broadly neutralizing antibodies (bnAbs) that bind to the viral envelope glycoprotein (Env). Poor binding of Env to unmutated precursors of bnAbs, including those of the VRC01 class, appears to be a major problem for bnAb induction. We engineered an immunogen that binds to VRC01-class bnAb precursors and immunized knock-in mice expressing germline-reverted VRC01 heavy chains. Induced antibodies showed characteristics of VRC01-class bnAbs, including a short CDRL3 (light-chain complementarity-determining region 3) and mutations that favored binding to near-native HIV-1 gp120 constructs. In contrast, native-like immunogens failed to activate VRC01-class precursors. The results suggest that rational epitope design can prime rare B cell precursors for affinity maturation to desired targets.

Subfields: Epidemiology, Immunology, Virology

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In Epidemiology

1. Ian A. Wilson
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1. Shane Crotty
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Citations in the corpus

• Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles (2016, positive): “A 60-meric LS nanoparticle presenting an engineered gp120 core lacking variable loops (V1V2 and V3) and inner domain has been used to target the germline precursors of VRC01 (refs 37,38), a CD4-binding site (CD4bs)-directed bNAb 51 .”
• Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens (2017, background): “Unimmunized VRC01gH mice possess eOD-GT8 binding B cells at a frequency of 1 in 100 naive B cells (Figure S1A), with the frequency of VRC01-class precursors estimated tobe1 in 1,250 (Jardine et al., 2015).”
• Glycan-Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies (2018, positive): “We also determined the frequency of CD4bs-specific B cells among eOD-GT8-specific IgG+ B cells (B220+IgG+) by using fluorophore-labeled eOD-GT8 and eOD-GT8 KO monomers as probes (Jardine et al., 2015; Sok et al., 2016; Tian et al., 2016).”
• Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization (2018, background): “…Env trimers (de Taeye et al., 2015; Pauthner et al., 2017; Sanders et al., 2015; Sok et al., 2017; Torrents de la Peña et al., 2017; Voss et al., 2017) and germline-targeting immunogens (Dosenovic et al., 2015; Jardine et al., 2015, 2016; ublished by Elsevier Inc. commons.org/licenses/by/4.0/).”