When human immunodeficiency virus-1 (HIV-1) infects humans it can cause a serious disease that damages the immune system. Currently there is no cure for this disease and there are no vaccines available to halt the spread of the virus. Researchers are hoping to be able to develop a single vaccine that can protect individuals against every form (or strain) of HIV-1, but this has proved difficult because many different versions of the virus exist.

An effective vaccine triggers long-lasting immunity to a particular virus or microbe by activating the production of proteins called antibodies that identify and help to destroy the threat. Research has shown that most individuals infected with HIV-1 produce antibodies that can only recognize a few HIV strains. However, there are rare individuals who produce “broadly neutralizing antibodies”; that is, antibodies that can recognize and help to kill 90% or more of HIV-1 strains. Understanding how broadly neutralizing antibodies are produced in infected individuals may aid the development of a vaccine that can protect others from the many circulating strains of HIV.

When an individual encounters a virus, immature antibodies are modified to generate mature antibodies that bind more effectively to specific virus proteins. Here, Scharf et al. investigated how a class of broadly neutralizing antibodies called VRC01-class antibodies, which bind to an HIV protein called gp120, are produced. The experiments used a technique called X-ray crystallography to reveal the three-dimensional structures of immature versions of these antibodies when they are bound to gp120.

Scharf et al. discovered that, unlike most antibodies, the overall final structure of VRC01 antibodies is formed before the antibody matures. Instead of making large changes to the structure of these antibodies, the maturation process makes VRC01-class antibodies become more positively charged, which allows them to bind to gp120 proteins on a wider variety of HIV viruses. These findings suggest that it may be possible to use modified gp120 proteins in vaccines to trigger the production of broadly neutralizing antibodies against HIV.

The HIV-1 envelope (Env) spike, a trimer of gp120-gp41 heterodimers, is the only target of neutralizing antibodies (Abs). Rapid mutation combined with structural features of the Env trimer that hide conserved features of the HIV-1 spike result in induction of mainly strain-specific neutralizing Abs in most infected individuals. However, broadly neutralizing Abs (bNAbs) evolve in a minority of HIV-1–infected individuals after several years of infection. These Abs are of considerable interest for HIV-1 therapeutic efforts because they can prevent and treat infection in animal models (reviewed in ([West et al., 2014]) and exhibited efficacy against HIV-1 in a human clinical trial (Caskey et al., 2015). Thus, it is believed that an immunogen that could elicit bNAbs would induce a protective immune response against infection by HIV-1.

Highly potent bNAbs against the conserved CD4-binding site (CD4bs) on gp120 that were derived from the VH1-2*02 variable heavy chain (HC) gene have been isolated from at least nine HIV-1–infected individuals (Scheid et al., 2011; Wu et al., 2010; Zhou et al., 2013; 2015; Wu et al., 2011; Georgiev et al., 2013). These bNAbs exhibit unusually high levels of somatic hypermutation, with changes in both complementarity determining regions (CDRs) and framework regions (FWRs) (Klein et al., 2013). As exemplified by VRC01, the first such bNAb to be isolated (Wu et al., 2010), VRC01-class bNAbs share a common mode of gp120 binding in which the VH1-2*02-derived variable heavy (V_H) domain mimics CD4 (Wu et al., 2010; Zhou et al., 2010; 2013; 2015; Diskin et al., 2011). Signature features of the HCs of VRC01-class bNAbs that explain their derivation from the VH1-02*02 gene segment include Trp50_HC, Asn58_HC, and Arg71_HC; an additional signature residue, Trp100B_HC within CDRH3, is derived from the joining of the D and J gene segments to the VH gene segment during V(D)J recombination (Diskin et al., 2012). The variable light (V_L) domains of VRC01-class bNAbs, which can be derived from several different VL germline gene segments, require a short (five residues) CDRL3 loop to allow interactions with gp120 V5 and loop D (Diskin et al., 2012) and often include a deletion in CDRL1 to avoid clashes with an N-linked glycan attached to Asn276_gp120 (Zhou et al., 2010; 2013; Scharf et al., 2013). The LC contact residues of VRC01-like bNAbs and the short CDRL3 are not germline encoded (Diskin et al., 2012). Because VRC01-class bNAbs are highly potent, have demonstrated efficacy in animal and human trials, and evolved in multiple HIV-1–infected donors who were infected with different strains of HIV-1, they are considered a promising target for elicitation by vaccination with designed immunogens.

The first step in eliciting an Ab is binding to its precursor germline-encoded B cell receptor by an antigen or immunogen with adequate affinity to initiate B cell activation and affinity maturation (Batista and Neuberger, 1998). Although the unmutated VH1-2*02 gene segment includes the signature V_H domain residues for interacting with the CD4bs, germline-reverted versions of VRC01-class bNAbs do not bind to Env trimers or to gp120 (Scheid et al., 2011; Zhou et al., 2010; Diskin et al., 2012; Scharf et al., 2013; Hoot et al., 2013; Ota et al., 2012; McGuire et al., 2013). In previous studies, we investigated VRC01-class germline recognition of Env by solving a crystal structure of the clade A/E 93TH057 gp120 core bound to a half germline, half mature chimeric VRC01-class Ab (NIH45-46_CHIM) in which the inferred germline HC was paired with the mature LC to permit binding to an unmodified gp120 (Scharf et al., 2013). Two forms of designed gp120-based immunogens were subsequently engineered to bind and activate germline HC/LC VRC01-class B cell receptors: gp120 outer domain-only constructs (eOD-GT6 and eOD-GT8) (Jardine et al., 2013; 2015) and gp120s modified from the clade C 426c Env (McGuire et al., 2013; 2014; 2016). Crystal structures of the inferred germline Fab of VRC01 complexed with eOD-GT6 and NIH45-46_CHIM complexed with gp120 revealed a similar angle of approach for binding as mature Fabs and conservation of the signature VRC01-class interactions with gp120 residues (Scharf et al., 2013; Jardine et al., 2013). However, questions concerning germline B-cell receptor recognition of gp120 remained because neither structure represented a complex between a fully germline VRC01-class Ab and a complete gp120 core. Here, we present crystal structures of inferred germline VRC01-like Abs alone and complexed with 426c-based gp120 immunogen cores and compare and contrast their gp120 recognition with structures of mature VRC01-class Ab/gp120 complexes. The analyses shed insight on the evolution pathway by which Abs derived from VH1-2*02 germline mature towards broad recognition of the CD4bs on gp120 and provide structural information that will facilitate design of immunogens to elicit VRC01-class bNAbs.

The process by which B cells produce high-affinity Abs starts with antigen binding to an unmutated, germline B cell receptor produced by random joining of V, D, and J or V and J gene segments. Affinity maturation is the process by which Abs with higher antigen-binding affinity are created through somatic hypermutation of the germline B cell receptor (Victora and Nussenzweig, 2012). Many anti-HIV-1 bNAbs, including VRC01-class CD4bs bNAbs, are heavily somatically mutated, likely through successive rounds of hypermutation and selection of B cells in response to rapid mutation of HIV-1 Env (West et al., 2014; Klein et al., 2013). Mature VRC01-class bNAbs achieve nucleotide somatic mutation frequencies of 32% and 20% in HC and LC variable region genes, respectively, whereas the mutation frequencies of more typical affinity-matured human Abs rarely exceeds 10% (Kwong and Mascola, 2012). Although heavily somatically mutated, VRC01-class bNAbs are promising targets for vaccine design because they have evolved in multiple donors from a common human germline V_H gene segment, VH1-2*02, to recognize HIV-1 Env using conserved interactions (Scheid et al., 2011; Wu et al., 2010; Zhou et al., undefined; Zhou et al., 2013; Diskin et al., 2011; Zhou et al., 2010).

The first step in targeted attempts to raise VRC01-class bNAbs by immunization requires identification of an immunogen that binds to the germline configuration of the B-cell receptor, but germline-reverted versions of VRC01-like bNAbs generally do not bind HIV-1 Env (Scheid et al., 2011; Zhou et al., 2010; Diskin et al., 2012; Scharf et al., 2013; Hoot et al., 2013; Ota et al., 2012; McGuire et al., 2013; Jardine et al., 2013). Although antigens designed to bind to predicted unmutated germline precursors of VRC01-class bNAbs have been constructed and evaluated (McGuire et al., 2013; 2014; 2016; Jardine et al., 2013; 2015; Dosenovic et al., 2015), structural comparisons of germline and mature versions of VRC01-class bNAbs bound to gp120-based immunogens were not available. Here, we report the results of structural studies of immunogens that bind to the inferred germline precursors of VRC01-class bNAbs, discovering both general principles and details of interactions that can guide structure-based immunogen design.

A surprising finding revealed by our structural comparisons of germline and mature VRC01-class Fabs was an increase in electropositive surface potential in the antigen-combining site for the mature Fab compared with the germline-inferred Fab, which we observed in the three VRC01-class Abs (NIH45-46, 3BNC60, and VRC01) for which germline and mature Fab structures were available for calculating electrostatic potentials. This marked shift to a more electropositive antigen combining site may also occur in other VRC01-class bNAbs, particularly those whose LCs are derived from the LC germline KV1-33 gene segment. Mature VRC01-class bNAbs appear on average to have a higher net nominal charge of their V_HV_L domains (+4.9) than the average human Ab (+3.1; as calculated from sequenced human B-cell repertoires) (Table 2) (Rubelt et al., 2012), and the VH1-2*02 gene segment yields a sequence with a nominal net charge of +5, higher than the average human V_H gene segment (+2 to +3). However, the KV1-33 LC germline gene segment, used by some VRC01-class Abs, yields a protein sequence with a nominal net charge of -4, in contrast to the KV3-20 gene segment (utilized by other VRC01-class Abs) with a net charge of zero. Perhaps to compensate for these negative charges, after maturation of the KV1-33–derived VRC01-class bNAbs 3BNC117, VRC-CH31, and 12A12, the portions of the V_L domain encoded by the KV1-33 gene segment have net nominal charge changes of +5, +3, and +6, respectively.

The trend towards increased electropositivity with Ab maturation does not apply to all HIV-1 Env-specific Abs: maturation of CH58, a non-neutralizing Ab against the gp120 V2 loop that was raised by vaccination in the RV144 trial (Liao et al., 2013), did not involve a shift to increased electropositive character (Figure 8—figure supplement 1), consistent with its epitope being centered on a positive residue, Lys169_gp120, within the gp120 V2 loop (Nicely et al., 2015). However, the developmental pathway of potent V1V2-directed bNAbs involves increased positivity of the CDRH3 loop, which starts as highly electronegative in part due to sulfated tyrosines, but accumulates positive charges during maturation that partially compensate for the negatively-charged sulfates (Doria-Rose et al., 2014). A trend towards electropositive combining sites in mature HIV-1 bNAbs could rationalize their tendencies towards polyreactivity (binding more than one antigen), which has been observed at higher frequencies for broadly neutralizing, as compared with non-neutralizing, Abs against HIV-1 (Liu et al., 2015). For example, increased non-specific binding to cardiolipin and nucleic acids, negatively-charged antigens commonly used in polyreactivity assays, correlates with polyreactive properties of Abs (Mouquet et al., 2010).

We suggest that evolution of increased electropositivity during maturation of VRC01-class bNAbs (and perhaps other HIV-1 bNAbs; Figure 8—figure supplement 1) facilitates interactions with heavily glycosylated HIV-1 Env spikes that include complex N-linked glycans containing negatively charged sialic acids. Indeed, somatic hypermutation to increase electropositivity of an Ab combining site may be a strategy utilized by Abs against other viruses containing heavily glycosylated Env proteins, such as influenza and Ebola. In the case of VRC01-class bNAbs, this strategy may be part of a multi-pronged approach of the humoral immune response against the CD4 binding site of HIV-1 for accommodating and/or for avoiding the N-linked Env glycan attached to Asn276_gp120, a site that can include complex-type N-glycans (Behrens et al., 2016), with other strategies including deletions to shorten CDRL1 and increasing CDRL1 flexibility by somatic mutations to glycine (Zhou et al., 2013). In addition to these steric considerations for potentially unfavorable interactions between CDRL1 and the Asn276_gp120-linked glycan, the neutral or negatively charged character of the germline Fab combining sites provides a structural justification for the necessity to eliminate the Asn276_gp120- and Asn463_gp120-linked N-glycans from eOD- and gp120-based immunogen candidates to achieve binding to inferred germline B-cell receptors (McGuire et al., 2013; Jardine et al., 2013; 2015; McGuire et al., 2014; 2016). The structures presented here, taken together with immunogen requirements for achieving germline Ab binding and previous structural analyses of mature VRC01-class Abs (Zhou et al., undefined; Zhou et al., 2010; 2013; McGuire et al., 2013; 2014; 2016; Jardine et al., 2013; 2015), suggest that the initiating antigen(s) in a natural pathway to induce VRC01-class Abs in HIV-1–infected individuals involve viral variants that lack the Asn276_gp120 (5% of HIV-1 strains in the Los Alamos Database) and the Asn463_gp120N-glycans (~80% of HIV-1 strains in the Los Alamos Database) (http://www.hiv.lanl.gov/content/index). Alternatively, a natural VRC01-class eliciting antigen could be the result of glycan heterogeneity within a single HIV-1 strain that produced variants containing high mannose, rather than complex-type, N-glycans at Asn276_gp120 and/or Asn463_gp120, consistent with observations of glycan heterogeneity at individual N-linked glycosylation sites within single HIV-1 strains (Go et al., 2011; Behrens et al., 2016).

Although antibody-antigen recognition modes represent a continuum of binding mechanisms, germline precursors to affinity-matured Abs have been suggested to display structural flexibility to allow expanded antigen recognition through induced fit mechanisms, whereas affinity maturation through somatic hypermutation was assumed to convert recognition to a lock-and-key model (Foote and Milstein, 1994; Wedemayer et al., 1997; Thorpe and Brooks, 2007). Induced fit modes of Ab-antigen recognition involve changes in the conformations of backbone and sidechain atoms of both the Ab and the antigen (Blackler et al., 2011; Li et al., 2007; Rosen et al., 2005; Sinha and Smith-Gill, 2005; Verdaguer et al., 1996), with large changes in the Ab usually occurring in the CDR loops. By contrast, lock-and-key recognition involves a minimum of conformational changes between the bound and unbound states of the antigen and Ab. Here, we showed that for the VRC01 class of CD4bs bNAbs, the maturation pathway for antigen binding from germline Ab to affinity-matured Ab does not involve changes from induced fit to lock-and-key binding mechanisms. Instead, the 426c gp120 immunogens bind NIH45-46_GL and 3BNC60_GL without requiring notable conformational changes in either the Ab or the antigen; thus both are largely preformed for binding. The largely lock-and-key binding mechanism for germline VRC01-class recognition of antigen may be rationalized by the fact that germline VRC01-class CD4bs Abs face major steric constraints when binding to HIV-1 Env trimer due to the recessed location of the epitope and its shielding by glycans from the target and adjacent gp160 monomers (West et al., 2014; Zhou et al., 2015). VRC01-like CD4bs bNAbs bind Env at an acute angle using mostly CDRs and FWRs of V_H in part because these steric constraints likely do not allow a Fab to bind perpendicular to the CD4bs on a closed Env trimer without clashes with the adjacent trimer subunit. These constraints may also not permit bNAbs or their germline precursors to undergo the major conformational changes characteristic of induced-fit binding and instead select for rare Ab sequences that are preformed to recognize their epitope in this highly sterically-constrained setting. The lock-and-key binding mechanism of VRC01-class recognition also may reflect that the binding interaction is dominated (relative to other Abs) by V_H domain FWRs, and that these would be unlikely to undergo large induced-fit conformational changes.

Structural analyses of germline and mature versions of the non-neutralizing HIV-1 Ab CH58 showed a more typical path for Ab-antigen recognition; the germline precursor used a combination of induced fit and lock-and-key binding modes to recognize a V2 peptide antigen: its CDRL2 loop was preformed for binding but CDRL3 changed conformation upon antigen binding (Nicely et al., 2015). The conformation of CDRL3 became fixed in mature CH58 through limited somatic mutation compared with VRC01-class Abs (11 total substitutions in CH58 V_HV_L) (Nicely et al., 2015). Thus, the conversion from induced fit to lock-and-key binding may be applicable for HIV-1 Abs such as CH58 that include the relatively small numbers of somatic mutations typical for most Abs, but not for VRC01-class Abs, whose maturation process involves a much higher number (>60) of mutations.

The finding of what can be described as lock-and-key recognition for germline Fabs binding to the 426c gp120 immunogens contrasts with recognition of unmodified gp120s used for structural studies of complexes with mature VRC01-class bNAbs that do not bind or bind only poorly to germline Abs. For example, when bound to the unmodified 93TH057 gp120, the CDRH3 of the germline HC in the NIH45-46_CHIM-93TH057 complex structure was partially disordered, presumably to avoid clashes with a gp120 not optimized for binding to germline Abs (Scharf et al., 2013). An example of structural rearrangements in a mature VRC01-class bNAb bound to an unmodified gp120 is illustrated by a study of the Ala61_HCPro substitution in the C” β-strand of the β-sheet framework in the V_H domains of the 3BNC60/3BNC117 HIV-1 bNAbs. This substitution is required for maximal neutralization potency of the mature bNAbs, yet it disrupts the C” β-strand of the V_H domain in the unbound Fab and decreases its thermal stability (Klein et al., 2013), with the β-sheet framework being restored through a large conformational change when the mature Fab binds gp120 (Zhou et al., 2013; Klein et al., 2013). Taken together, the findings of what appears to be lock-and-key style germline Fab recognition with increased flexibility upon maturation for the highly somatically-mutated VRC01-class bNAbs contradict the assumption of induced fit for germline Ab recognition and lock-and-key fit for mature Ab binding (Foote and Milstein, 1994; Wedemayer et al., 1997; Thorpe and Brooks, 2007). This assumption was also challenged by studies of the maturation of other HIV-1 Abs: for example, CH103, a non-VRC01-class CD4-binding site bNAb, exhibits changes in the relative orientation of its V_H and V_L domains during maturation (Fera et al., 2014), and the HIV-1 gp41-directed bNAb 4E10 exhibits increased flexibility in its combining site during maturation (Finton et al., 2014). Thus, the rare events that result in evolution of HIV-1 bNAbs can fall outside of typical Ab maturation pathways.

We speculate that 426c-based immunogens are able to bind germline precursors of VRC01-class bNAbs as a complete gp120 core because they can engage the unbound conformation of these Abs. This may allow the gp120-based immunogens to overcome a loss of binding affinity due to slow on-rates in the context of the already weak binding affinities of immature B cell receptors. The improved binding of the 426c-based gp120 immunogens to some germline VRC01-class Abs upon removal of the V1V2 and V3 loops from the 426c.TM1△V1-3 and 426c.TM4△V1-3 gp120s could result from the removal of steric occlusion by the variable loops (also not present in the eOD immunogens (Jardine et al., 2013; 2015), and which may be flexible in the context of a gp120 or eOD), removal of glycans attached to these loops, or a combination of these factors. Thus, our results suggest implementation of a general strategy in which a germline-binding antigen is designed to be electrostatically compatible with the neutral or negatively charged antigen-binding surfaces of germline VRC01 Fabs and to fit in lock-and-key mode to the combining site of a germline Fab, with consideration paid to the slightly different angles of approach reported here for germline Fab binding to the gp120-based immunogens. The general principles established here for germline VRC01-class recognition of gp120 can be used to guide efforts to design and produce immunogens capable of eliciting broad and potent CD4bs Abs of the VRC01 class in uninfected people, facilitating the development of an efficacious vaccine to protect from HIV-1 infection.

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Author details

1. Louise Scharf

   Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

   Present address

   23andMe, Mountain View, United States

   Contribution

   LSc, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

2. Anthony P West Jr

   Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

   Contribution

   APW, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

3. Stuart A Sievers

   Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

   Present address

   Kite Pharma, Santa Monica, United States

   Contribution

   SAS, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

4. Courtney Chen

   Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

   Contribution

   CC, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

5. Siduo Jiang

   Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

   Present address

   D. E. Shaw Research, New York, United States

   Contribution

   SJ, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

6. Han Gao

   Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

   Contribution

   HG, Acquisition of data, Contributed unpublished essential data or reagents

   Competing interests

   No competing interests declared.

7. Matthew D Gray

   Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   MDG, Contributed unpublished essential data or reagents

   Competing interests

   No competing interests declared.

8. Andrew T McGuire

   Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   ATM, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   No competing interests declared.

9. Johannes F Scheid

   Laboratory of Molecular Immunology, The Rockefeller University, New York, United States

   Contribution

   JFS, Contributed unpublished essential data or reagents

   Competing interests

   No competing interests declared.

10. Michel C Nussenzweig

    1. Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    2. Howard Hughes Medical Institute, The Rockefeller University, New York, United States

    Contribution

    MCN, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    MCN: Reviewing editor, eLife.

11. Leonidas Stamatatos

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States

    Contribution

    LSt, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    No competing interests declared.

12. Pamela J Bjorkman

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

    Contribution

    PJB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    bjorkman@caltech.edu

    Competing interests

    No competing interests declared.

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