Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development

Abstract

Induction of HIV-1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV-1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV-1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV-1 transmission to development of bnAbs. This work has revealed that a virus-antibody "arms race" occurs in which a HIV-1 transmitted/founder (TF) Env induces autologous neutralizing antibodies that can not only neutralize the TF virus but also can select virus escape mutants that in turn select affinity-matured neutralizing antibodies. From these studies has come a picture of bnAb development that has led to new insights in host-pathogen interactions and, as well, led to insight into immunologic mechanisms of control of bnAb development. Here, we review the progress to date in elucidating bnAb B cell lineages in HIV-1 infection, discuss new research leading to understanding the immunologic mechanisms of bnAb induction, and address issues relevant to the use of this information for the design of new HIV-1 sequential envelope vaccine candidates.

Keywords: HIV neutralization; HIV vaccine; co-evolution.

Figure 1

Sites of vulnerability on the HIV‐1 Env glycoprotein spike. The structure of a HIV‐1 prefusion trimer (PDB: 4TVP) is displayed with gp120 and gp41 protomers colored in blue and beige respectively. Epitope mapping of multiple broadly neutralizing antibodies has identified six sites of vulnerability of the HIV‐1 Env glycoprotein: the V1V2 loop (red); the base of the V3 loop (green); the CD4‐binding site (orange); the interface between gp120 and gp41 proteins (magenta); the fusion peptide region (yellow), and the membrane proximal external region (MPER, brown). Both the V1V2 and the V3 loop bnAb epitopes include direct contact with glycans. The MPER near the base of the Env trimer, the transmembrane and the cytoplasmic domains have only limited structural information and are highlighted for reference (red and sand cylinders and green sticks). Figure derived from structure described by Pancera et al.59

Figure 2

Neutralizing activity of CH103 lineage antibodies against longitudinal autologous virus quasi‐species variants. Heat map analysis of neutralization data generated from 43 pseudoviruses (X axis) and 12 CH103 lineage mAbs (Y axis). Neutralization potency (IC₅₀) is shown in different shades of color as indicated in the legend, from white (>50 μg/mL) to dark red (<0.5 μg/mL). CH103 lineage mAbs are ordered based on their phylogenic relationship as described in Liao et al.,17 from the unmutated common ancestor (top) to the most mutated CH103 bnAb (bottom). Less mature CH103 lineage antibodies (UCA‐IA4) neutralized only autologous viruses, whereas more somatically mutated mAbs (IA3‐CH103) acquired broad neutralization. Autologous neutralization of bnAb precursors was limited to viruses isolated early during the course of infection (●) whereas affinity matured CH103 lineage bnAbs retained the ability to neutralize autologous viruses isolated up to week 136 (○)

Figure 3

Mechanism of cooperation between B cell lineages in inducing HIV‐1 broadly neutralizing antibodies. The transmitted/founder virus (green) evolves under pressure of autologous neutralizing antibodies. Among them are lineages that progress to neutralization breadth (red) and cooperating lineages (blue) that target the same epitope. The cooperating lineage selects for virus escape mutants that are more sensitive to neutralization of the evolving broadly neutralizing antibody lineages, thus providing sustained stimulation to bnAb B cell precursors and affinity maturation

Figure 4

Effects of clonal maturation on CH235 VH1‐46 bnAb lineage antibody recognition of the CD4‐binding site of vulnerability. (A) Co‐crystal structures of the antigen‐binding fragments (Fabs) of CH235, CH235.9 and CH235.12 antibodies with core gp120. Structures are shown in ribbon diagram, with gp120 in gray and residues altered by somatic hypermutation in stick representation colored by time‐of‐appearance. The V_H domain mimicked CD4 in Env binding and the gp120 Env‐antibody orientation was determined early in bnAb lineage ontogeny and was maintained throughout clonal evolution. (B) The footprints of the CH235, CH235.9 and CH235.12 on gp120 are shown in green, brown, and purple respectively. The footprint of the CD4 supersite of vulnerability is highlighted in yellow. Targeting precision to the CD4 supersite of vulnerability correlated with neutralization breadth. Figure adapted from Bonsignori et al. 16 and used with permission

Figure 5

B‐cell lineage‐based approach to vaccine design. Affinity matured broadly neutralizing antibodies (bnAbs) and bnAb precursors are isolated from HIV‐1 infected donors using methods such as memory B cell cultures or antigen‐specific B cell sorting (step 1). Based on known bnAb sequences, next‐generation sequencing can be used to retrieve numerous V_HDJ_H and V_LJ_L clonally related rearrangements. If appropriate longitudinal samples are available, it is possible to define the full lineage phylogeny and infer the unmutated common ancestor (UCA) and early maturation intermediate antibodies (IA) (step 2). Recombinant monoclonal antibodies expressing the bnAb precursor V_HDJ_H and V_LJ_L rearrangements from UCA and through IAs can then be used to design HIV‐1 immunogens that will engage and select for B cells with BcRs evolving to neutralization breadth. Studying the co‐evolution of autologous virus and bnAb lineages and the selection operated by cooperating lineages on autologous virus has in many cases identified Env immunogens that can engage the bnAb germline UCA antibody, and defined which HIV‐1 Envs participated in bnAb lineage development, thus enabling the design of sequential immunogens (step 3)

Figure 6

Mechanism of diversion of cross‐reactive memory B cells by transmitted founder virus. Naïve B cells can be triggered by antigens derived from the microbiota or other environmental antigens and give rise to a somatically mutated clonal pool of memory B cells that undergoes affinity maturation against the cognate antigen (blue pathway). Among the microbiota‐induced memory B cells, we have demonstrated that some cells can cross‐react with HIV gp41 Env.90, 91, 92 Transmitted/founder virus Env can engage these mutated cells, even if the unmutated ancestor naïve B could not, and diverge clonal evolution to affinity maturation against Env (green pathway). This mechanism resulted in a dominant expansion of non‐neutralizing gp41‐microbiota cross‐reactive memory B cells

Figure 7

Immunogen design for CDR H3‐binding CD4bs bnAbs. Interactions between evolving virus and the developing CH103 clonal lineage mapped onto models of CH103 developmental variants and contemporaneous virus as indicated. The outer domain of HIV gp120 is shown in worm representation, with thickness and color (white to red) mapping the degree of per‐site sequence diversity at each time point. Models of antibody intermediates are shown in cartoon diagram, with somatic mutations at each time‐point highlighted in spheres and colored according to first appearance of each mutation in IAs and CH103 bnAb as indicated. Paratope residues are shown in surface representation and colored by their chemical types as indicated. Figure adapted from Liao et al.17 and used with permission

Figure 8

Immunogen design for concurrent elicitation of CD4 mimic and CDR H3‐binder bnAbs. (A) Phylogenetic tree of the CH235 lineage, colored by first time (weeks postinfection) from which sequences were obtained. Cooperation with the CH103 lineage was exerted by bnAb precursors, such as the CH235 mAb, which displayed limited breadth. The structures of CH235, CH235.9 and CH235.12 Fabs in complex with gp120 (gray) show the residues altered by somatic hypermutation colored by time of appearance. As maturation progressed, CH235 lineage antibodies broaden their spectrum of neutralization to 90% for CH235.12. Neutralization dendrograms display single mAb neutralization of a genetically diverse panel of 199 HIV‐1 isolates. Coloration is by IC ₅₀. (B) Heat map analysis of selected autologous gp120 Env quasi‐species variants binding to CH235 and CH103 lineage antibodies. Strength of binding (LogAUC) is shown in different shades of color as indicated, from white (<0.09) to dark red (>12.9). The gp120 Envs is a selection of immunogens optimized to induce both CH235‐ and CH103‐like bnAbs based on their ability to progressively engage members of both antibody lineages with increasing binding strength. The M5 and M11 gp120 Envs are CH505 TF loop D mutants that best bound to the UCA of the two lineages.16 Figures adapted from Bonsignori et al.16 with permission

Figure 9

Immunogen design for V3‐glycan broadly neutralizing antibodies. An immunization strategy to elicit DH270‐like V3 glycan bnAbs is composed of three steps. First, prime with an immunogen that binds to the UCA. We have identified a synthetic Man₉ V3 glycopeptide as a candidate immunogen (Bonsignori M., Alam S. M. and Haynes B. F., unpublished). Clonal differentiation subsequent to priming will lead to the introduction of somatic mutations, including improbable mutations critical for clonal maturation toward neutralization breadth (green). Second, boosting with an immunogen that engages of DH270.IA4‐like antibodies and select for the these improbable mutations, providing an evolutionary advantage to a subdominant response. Third, boost with Env immunogens with longer V1 loops, as the ability to neutralize viruses with longer V1 loops was correlated with broader neutralization in the DH270 lineage (Bonsignori M, Korber B. T. and Haynes B.F., unpublished)