Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies

Abstract

After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1 vaccine is challenging, including the extraordinary genetic diversity of HIV-1 and its complex mechanisms of immune evasion. HIV-1 envelope glycoproteins are poorly recognized by the immune system, which means that potent broadly neutralizing antibodies (bnAbs) are only infrequently induced in the setting of HIV-1 infection or through vaccination. Thus, the biology of HIV-1-host interactions necessitates novel strategies for vaccine development to be designed to activate and expand rare bnAb-producing B cell lineages and to select for the acquisition of critical improbable bnAb mutations. Here we discuss strategies for the induction of potent and broad HIV-1 bnAbs and outline the steps that may be necessary for ultimate success.

Fig. 1. Model of broadly neutralizing antibody development in humans.

In individuals infected with HIV-1, viral diversification of envelope (Env) sequences was found to be required for broadly neutralizing antibody (bnAb) development. From this work came the concept of transmitted/founder Envs that initiate the infection and B cell lineage design whereby sequential immunogens are chosen from autologous evolved viruses that induced bnAbs, or are structurally designed to have affinity gradients across maturing lineage members and to select for desired mutations to favour bnAb development. bnAb development follows a ‘jackpot effect’, where each individual with HIV-1 who makes bnAbs has only one or very few bnAb B cell lineages that have made it through a tortuous bnAb maturation pathway requiring multiple rare events stimulated by evolving virus.

Fig. 2. Host immunoregulatory control abnormalities in individuals infected with HIV-1 who make broadly neutralizing antibodies.

In studies of cohorts of individuals positive for HIV-1, those who make broadly neutralizing antibodies (bnAbs) have high levels of circulating CD4⁺ T follicular helper (T_FH) cells, low levels of CD4⁺ regulatory T (T_reg) cells and circulating T follicular regulatory (T_FR) cells, high levels of plasma autoantibodies and low levels of functional natural killer cells. Increased availability of CD4⁺ T_FH cells and reductions in the numbers of functional T_reg cells and natural killer cells, both of which constrain germinal centre responses to reduce autoantibody production, may enable enhanced B cell somatic hypermutation and repertoire diversification. In addition, individuals infected with HIV-1 who make bnAbs have perturbations in their B cell IgG repertoires such that B cell receptors (BCRs) with longer heavy chain complementarity determining region 3 (HCDR3s) and increased autoreactivity can expand. Thus, HIV-1 infection results in a permissive immunologic environment that favours eventual bnAb development.

Fig. 3. Complexity of a prototype HIV-1 vaccine for the induction of broadly neutralizing antibodies.

HIV-1 envelope (Env) trimer with targets for broadly neutralizing antibodies (bnAbs) shown in colour. A polyclonal multi-B cell lineage response requires development of bnAbs binding to the CD4 binding site and to at least two other epitopes, such as V2 glycan, V3-glycan patch, fusion domain or membrane proximal external region (MPER) sites. Fab-dimerized glycan (FDG) antibodies bind to high mannose residues at multiple sites on Env. Figure derived from structure described by Pancera et al..

Fig. 4. Strategies for the design of HIV-1-targeted broadly neutralizing antibody immunogens.

B cell lineage immunogen design (upper right) uses insights into HIV-1 virus/broadly neutralizing antibody (bnAb) B cell co-evolution to inform the design of envelope (Env)-based immunogens that can recapitulate generation of similar bnAbs by vaccination. B cell lineage immunogen design starts by isolating a bnAb-producing B cell clone from an individual infected with HIV-1, sequencing its B cell receptors (BCRs) to identify clonal members and, then computationally reconstructing the maturation history of the bnAb. The maturation pathway from the inferred unmutated common ancestor (UCA) antibody (representing the naive bnAb B cell receptor (BCR)) through inferred ancestral intermediates to the bnAb serves as a molecular guide for HIV-1 vaccine design. UCA and inferred antibody intermediates serve as templates for design of immunogens that bind with high affinity. Immunogens can be designed through germline-targeting (upper left), structure-based immunogen design (lower left) and mutation-guided immunogen design (lower right). The goal is for sequentially administered immunogens to provide a selective advantage in the germinal centre to B cells that follow similar desired evolutionary trajectories. Because bnAb UCAs rarely bind with high affinity to unmodified autologous Envs, priming immunogens frequently must be designed with epitope modifications (for example, the shortening of variable loops, or removal of key glycans) in an approach called germline-targeting (upper left). Germine-targeting is based on selection of a transmitted/founder virus or a specifically selected or designed Env immunogen that can bind to a UCA^,,,,. This can be achieved through in vitro selection techniques where UCAs are used to bind and select high-affinity Env antigens from a library of Env variants. These Env ligands are then used to isolate antibodies from the human immunoglobulin repertoire to identify a polyclonal mixture of putative bnAb precursors. A germline-targeting Env antigen can then be re-designed to improve its affinity for many of the isolated putative bnAb precursors using mutation-guided immunogen design and structure-based immunogen design. Mutation-guided immunogen design aims to identify the improbable mutations in bnAbs that are not routinely generated by somatic hypermutation but are critical for broad neutralization. These are then used to inform the design of immunogens that can specifically select for these mutations. Structure-based immunogen design is based on the determination of bnAb–Env complexes that provide atomic-level information that is necessary to computationally model specific bnAbs as templates for immunogen design. These inform the modifications for improving Env immunogen binding to bnAbs or bnAb precursors. Structure-based immunogen design is utilized to inform all stages of the vaccine design strategy.

Fig. 5. Construction of simian-human immunodeficiency viruses containing clinically relevant primary HIV-1 Env immunogens.

Critical to simian-human immunodeficiency virus (SHIV) design is selection of primary or transmitted/founder HIV-1 envelope (Env) immunogens that exhibit features of clinically relevant viruses. For SHIV construction, a mutation at Env position 375 is made to facilitate macaque CD4⁺ T cell engagement. A HIV transmitted/founder or other Env immunogen is engineered to be expressed on the surface of a simian immunodeficiency virus (SIV) virion to form a chimeric SHIV. In this manner, virtually any HIV-1 Env can be used to produce a SHIV for testing for the ability to induce broadly neutralizing antibodies (bnAbs) in the setting of lentiviral infection.