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. Author manuscript; available in PMC: 2016 Jan 14.
Published in final edited form as: Virology. 2015 Oct 1;486:116–120. doi: 10.1016/j.virol.2015.08.002

Binding of inferred germline precursors of broadly neutralizing HIV-1 antibodies to native-like envelope trimers

Kwinten Sliepen 1,*, Max Medina-Ramírez 1,*, Anila Yasmeen 2, John P Moore 2, Per Johan Klasse 2, Rogier W Sanders 1,2,#
PMCID: PMC4712445  NIHMSID: NIHMS749754  PMID: 26433050

Abstract

HIV-1 envelope glycoproteins (Env) and Env-based immunogens usually do not interact efficiently with the inferred germline precursors of known broadly neutralizing antibodies (bNAbs). This deficiency may be one reason why Env and Env-based immunogens are not efficient at inducing bNAbs. We evaluated the binding of 15 inferred germline precursors of bNAbs directed to different epitope clusters to three soluble native-like SOSIP.664 Env trimers. We found that native-like SOSIP.664 trimers bind to some inferred germline precursors of bNAbs, particularly ones involving the V1/V2 loops at the apex of the trimer. The data imply that native-like SOSIP.664 trimers will be an appropriate platform for structure-guided design improvements intended to create immunogens able to target the germline precursors of bNAbs.

To be effective, a HIV-1 vaccine should elicit bNAbs that target the trimeric Env spike on the virion surface (van Gils and Sanders, 2014). No Env immunogen has been able to elicit bNAbs in animals or humans, but ~20% of HIV-1-infected patients do eventually develop these antibodies after ~2–3 years, and some exceptional patients develop bNAbs within a year (van den Kerkhof et al., 2014). Longitudinal analyses have shown that bNAbs generally emerge through a co-evolutionary process that is driven by iterative cycles of HIV-1 escape from more narrowly focused NAbs, followed by renewed Ab affinity maturation (Doria-Rose et al., 2014; Liao et al., 2013).

To generate bNAbs by vaccination, it may be necessary to mimic such affinity maturation pathways (Haynes et al., 2012). Initiating any particular bNAb lineage requires activating the naïve B cells through their B cell receptor, i.e. the unmutated germline antibody (Haynes et al., 2012). For this to happen in a vaccine setting, the Env-based immunogen should, therefore, be capable of binding germline antibodies that have the potential to evolve into bNAbs. A complication is that most HIV-1 isolates appear incapable of interacting with the germline versions of bNAbs, which may be the outcome of how HIV-1 immune evasion strategies have evolved over time. In consequence, most recombinant Env proteins also cannot engage the inferred germline precursors of known bNAbs (gl-bNAbs) (Hoot et al., 2013; McGuire et al., 2013a), either because they adopt non-native conformations or because they are derived from viruses that also lack the required reactivity. The problem is not universal, in that some Env proteins based on autologous founder virus sequences isolated from the patient from which a particular bNAb was isolated can sometimes bind the germline precursor of that bNAb (Doria-Rose et al., 2014; Liao et al., 2013; Lynch et al., 2015). Furthermore, Env immunogens can be specifically engineered to have such properties (Dosenovic et al., 2015; Jardine et al., 2013, 2015; McGuire et al., 2013b).

Recently, several soluble, recombinant SOSIP.664 Env trimers from clades A (isolate BG505), B (isolate B41) and C (isolates ZM197M and DU422) have been described (Pugach et al., 2015; Sanders et al., 2013) (Julien et al. in press). Electron microscopy imaging, glycan profiling and antigenicity studies show that these SOSIP.664 trimers mimic the virion-associated Env trimer (Pritchard et al., 2015; Pugach et al., 2015; Sanders et al., 2013)(Julien et al. in press). In addition, the BG505 and B41 SOSIP.664 trimers have induced consistent NAb responses against the autologous tier 2 viruses, which has not been achieved by non-native Env immunogens (Sanders et al., 2015).

Whether native-like trimers such as the above SOSIP.664 proteins can interact with glbNAbs is clearly relevant to strategies intended to induce neutralization breadth. There are reasons to believe that trimers that do so may be desirable. First, only native-like trimers consistently present several quaternary structure-dependent bNAb epitopes at the V1V2-apex or the gp120/gp41 interface (Blattner et al., 2014; Huang et al., 2014; Sanders et al., 2013). Second, native-like trimers force the appropriate restrictions on the selection of Abs with the correct, trimer-compatible angles of approach, and thereby limit the exposure of immunodominant non-neutralizing epitopes that could interfere with the triggering of the desired bNAb germline (McGuire et al., 2014; Sanders et al., 2013; Tran et al., 2014). We have, therefore, assessed whether the BG505, B41 and ZM197M SOSIP.664 trimers can interact with a set of 15 gl-bNAbs.

Epitope-tagged SOSIP.664-D7324 or SOSIP.664-His trimers, expressed in 293F cells, were purified by PGT145 bNAb-affinity chromatography (Pugach et al., 2015). We used ELISA and, in some cases, surface plasmon resonance (SPR) methods to assess trimer binding to 15 gl-bNAbs, targeting five distinct Env epitope clusters: the CD4 binding site (CD4bs) (VRC01, 3BNC60, 1NC9, CH103, CH31); the glycan-dependent V3 cluster (PGT121, PGT128); the V1V2-apex (PG9, PG16, PGT145, VRC26.09, CH01) (Doria-Rose et al., 2014; West et al., 2014); the gp120/gp41 interface (PGT151, 35O22) (Blattner et al., 2014; Huang et al., 2014); gp41 (3BC315) (Lee et al., in press). We did not test binding to gp120 monomers or uncleaved gp140 proteins, since the mature versions of PG9, PG16, PGT145, VRC26.09, PGT151, 35O22 and 3BC315 have been reported to bind these proteins very inefficiently (Blattner et al., 2014; Doria-Rose et al., 2014; Huang et al., 2014; Ringe et al., 2013; Yasmeen et al., 2014)(Lee et al., in press).

The sequences of germline versions of PG9, PGT145, PGT151, 35O22, PGT128, 1NC9, 3BC315 were inferred using the IMGT/V QUEST online tools (Giudicelli et al., 2004) (Table 1). We note that PG9 and PG16 are clonal relatives and originate from the same germline precursor (Pancera et al., 2010). However, it is difficult to infer an accurate germline sequence of the long heavy chain complementarity-determining regions 3 (HCDR3) of these antibodies. Therefore, we used two different germline precursors of the PG9/16 lineage: gl-PG16 was based on the previously published sequence (Pancera et al., 2010) and gl-PG9 was inferred as described above. The gl-bNAb sequences were synthesized by Genscript, cloned into the pVRC8400 expression vector, transfected into 293F cells and then purified by a protein A/G agarose column (Thermo Scientific). The mature and germline versions of PG9, PG16 and PGT145 were expressed in the presence of exogenous tyrosylprotein sulfotransferase 1 (TPST1) to ensure they were tyrosine-sulfated (Julien et al., 2013). The germline versions of 3BNC60, VRC01, CH31, CH103, PGT121, CH01 and VRC26 were kindly provided by colleagues (Table 1). The ELISA for measuring Ab-trimer binding was modified from a published method (Sanders et al., 2013), as follows: 3 μg/ml of SOSIP.664-D7324 proteins were diluted in Tris-buffered saline pH 7.5 (TBS) containing 10% fetal calf serum (FCS), and captured on D7324 Ab-coated plates. Mature and gl-bNAbs were serially diluted in casein-blocking solution (Thermo Scientific). Half-maximal binding Ab concentrations (EC50) were derived using Graphpad Prism (version 5.01). All 15 mature bNAbs bound to all three SOSIP.664-D7324 trimers, which is mostly consistent with the antigenicity profiles reported previously (Pugach et al., 2015; Sanders et al., 2013) (Julien et al. in press) (Table 2). We note that, here, the mature versions of PGT151 and 35O22 were reactive with the B41 SOSIP.664 trimers in ELISA (Table 2), which was not seen in our previous study (Pugach et al., 2015). The difference may arise because we increased the assay sensitivity by using a higher input concentration of the B41 SOSIP.664-D7324 trimer (i.e., 3 μg/ml vs. 0.3 μg/ml, previously) and we used a different blocking solution (i.e., casein blocking solution vs. 2% milk, previously).

Table 1.

Putative gene usage and CDR3 sequences of the gl-bNAbs used in this study

Antibody VH-gene HCDR31 JH-gene VL-gene LCDR31 JL-gene Source Reference
PG9 V3-33*05 AREAGGPDYRNGYNYYDFWSGYYTYYYMDV3 J6*03 LV2-14*01 SSYTSSSTLV LJ3*02 IMGT N.A.
PG16 V3-33*05 AREAGGPIWHDDVKYYDFNDGYYNYHYMDV J6*03 LV2-14*01 SSYTSSSTLV LJ3*02 P. Kwong Pancera et al., 2010
PGT145 V1-8*01 GSKHRLRDYFLYNEYGPNYEEWGDYLATLDV2 J6*02 KV2-28*01 MQALQTPWT KJ1*01 IMGT N.A.
VRC26.09 V3-30*18 CAKDLGESENEEWAYDYYDFSIGYPGQDPRGVVGAFDIW J3*02 LV1-50*02 GTWDSSLSAGGVF LJ1-02 J. Mascola Doria-Rose et al., 2014
CH01 V3-20*01 GTDYTIDDQGIRYQGSGTFWYFDL J2*01 KV3-20*01 CQQYGSSPYTF KJ1*01 B. Haynes & H. Liao Bonsignori et al., 2011
VRC01 V1-2*02 ARGKNSDYNWDFQH J2*01 KV3-11*01 CQQYEFF KJ2*01 W. Schief Jardine et al., 2013
3BNC60 V1-2*02 ARQRSDFWDFDL J2*01 KV1-33*01 CQQYEFI KJ3*01 M. Nussenzweig Scheid et al. 2011
CH31 V1-2*02 ARAQKRGRSEWAYAH J4*02 KV1-33*01 CQQYETF KJ2*01 B. Haynes & H. Liao Wu et al., 2011
CH103 V4-59*01 SLPRGQLVNAYFDY J4*02 LV3-1*01 CQAWDSFSTFV LJ1*01 B. Haynes & H. Liao Liao et al., 2013
1NC9 V1-46*01 QDSDFHDGHGHTLRGMFDY2 J4*02 LV1-47*01 CAAWDDSLSGPVF LJ2*01 IMGT N.A.
PGT121 V4-59*01 TLHGRRIYGIVAFNEWFTYFYMDV J6*03 LV3-21*02 QVWDSRVITKWV LJ3*02 M. Nussensweig N.A.
PGT128 V4-39*07 FGGEVLRFLEWPKPAWFDP3 J5*02 LV2-8*01 SSYAGNWDVV LJ2*01 IMGT N.A.
PGT151 V3-30*04 ARMFQESGPPRLDRWSGRNYYYYYGMDV2 J6*02 KV2D-29*02 MQSKDFPLT KJ4*01 IMGT N.A.
35O22 V1-18*02 GLLRDGSSTWLPYL2 J4*02 LV2-14*02 SSYTSSSGCV LJ1*01 IMGT N.A.
3BC315 V1-2*02 PMRPVSHGIDYSGLFVFQF2 J3*01 LV2-23*02 CSYANYDKLI LJ3*01 IMGT N.A.
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1

The CDR3 length was defined based on www.bnaber.org when available or by www.imgt.org

2

The CDR3 sequence was taken from the mature version whenever the D gene generated by IMGT did not provide comprehensive matching to the mature nucleotide sequence.

3

The N region of the junction between the genes V and D was taken from the mature sequence, since reversion was not possible. The rest of the sequence was inferred by combining D and J genes.

Table 2.

Summary of EC50 values (in ng/ml) derived from D7324-capture ELISA with different SOSIP.664 trimers.

For comparison, midpoint neutralization concentrations (IC50 in ng/ml) of the sequence-matched Env-peudotyped viruses are also indicated.

BG505
B41
ZM197m
SOSIP.664 pseudovirus SOSIP.664 pseudovirus SOSIP.664 pseudovirus
Germline Mature Mature Germline Mature Mature Germline Mature Mature
V1V2 apex PG9 935 40 45* >25000 242 560 * 6769 103 393*
PG16 13100 31 8* >25000 65 80 * >25000 77 49*
PGT145 >25000 12 83* >25000 67 60 >25000 27 393*
VRC26.09 >25000 31 <10 >25000 1204 >25000 >25000 50 4*
CH01 640 58 301* 1003 44 N.D. >25000 2044 N.D.
CD4bs VRC01 >25000 9 70* >25000 34 1380 * >25000 7 329*
3BNC60 >25000 21 34 * >25000 55 11 >25000 58 77
1NC9 >25000 209 251* >25000 355 1961 >25000 128 1006*
CH103 >25000 179 2572* >25000 2412 >25000 18090 143 18222
CH31 >25000 13 14* >25000 32 26 >25000 48 358
gp41 and interface PGT121 >25000 61 15* >25000 147 920 * >25000 35 35*
PGT128 >25000 12 11* >25000 46 414 >25000 6 33*
V3 glycan PGT151 >25000 28 1 >25000 126 300 * >25000 30 2*
35O22 >25000 379 8 >25000 1052 >25000 >25000 463 2816*
3BC315 538 144 1259 * >25000 102 >25000 266 124 3549*
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graphic file with name nihms749754u1.jpg

*

IC50 values obtained from (Sanders et al., 2013) for BG505; (Pugach et al., 2015) for B41; (Julien et al., in press) for ZM197M

N.D.: not determined

The BG505 SOSIP.664-D7324 trimer bound to gl-PG9 and its somatic relative gl-PG16 (EC50: 1.0 and 15 μg/ml, respectively), its ZM197M counterpart bound to gl-PG9 (EC50: 6.8 μg/ml) but not gl-PG16, while the B41 trimer bound neither glPG9 nor glPG16 (Fig. 1 and Table 2). Compared to gl- PG16, gl-PG9 contains more tyrosines that are potentially sulfated, which could increase affinity for the cationic groove at trimer apex. This might explain the increased reactivity of gl-PG9 with BG505 and ZM197M SOSIP.664 trimers. The BG505 and B41 trimers also bound to gl-CH01 (EC50: 0.64 and 1.0 μg/ml respectively). Gl-VRC26 and gl-PGT145, which bind to a similar epitope as PG9 and PG16, but have entirely different CDRH3 loops and are derived from different germline genes, did not bind to any of the SOSIP.664 trimers. We observed a remarkably high affinity interaction between gl-3BC315 and the BG505 and ZM197M trimers (EC50: 0.27; 0.54 μg/ml respectively) (Fig. 1 and Table 2). We note, however, that the HCDR3 of the gl- and mature versions of 3BC315 were identical, since it was not possible to reliably infer the germline HCDR3 sequence from the mature version. As the HCDR3 of 3BC315 is known to make important hydrophobic contacts with the gp41/gp120 interface (Lee et al. in press), this interaction may contribute to the high affinity the gl-3BC315 antibody has for the BG505 and ZM197M trimers. However, as gl-3BC315 did not bind to the B41 trimers, there are complexities to the Ab-trimer binding events that remain to be understood, such as the involvement of topologically proximal glycans in either the formation or the occlusion of the epitope.

Figure 1.

Figure 1

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Representative binding curves of a panel of mature and gl-bNAbs tested in the same ELISA. We note that all mature (right) and gl-bNAbs (left) generated comparable and low background signals in this ELISA format (“mock”: the wells contained only 10% FCS in TBS), except gl-CH103, for which the background was considerably higher (“gl-CH103 mock”).

None of the three trimers bound the gl-bNAbs targeting the glycan-dependent V3 epitopes (PGT121 and PGT128). They also did not interact with the VRC01, 3BNC60, 1NC9 or CH31 gl-bNAbs against the CD4bs, perhaps because of the shielding effects of various trimer glycans. An example is the clash between the N276 glycan and the gl-VRC01 light chain (McGuire et al., 2013b). While gl- CH103 was prone to generating a high level of non-specific background signals in ELISA (Fig. 1, “gl-CH103 mock”), we did detect some specific binding of this antibody to the ZM197M trimers (EC50: 18.1 μg/ml) although not to their BG505 and B41 counterparts (Fig. 1 and Table 2).

To corroborate the binding of gl-PG16 to the BG505 SOSIP.664-D7324 trimers, we performed SPR analyses using the His-tagged version of the same trimers. The data were fitted with a bivalent model, and only binding parameters for the monovalent component in the bivalent model are given (Yasmeen et al., 2014). We confirmed that gl-PG16 bound to BG505 SOSIP.664-His trimers, although with a lower affinity (dissociation constant, Kd = 320nM) than mature PG16 (Kd = 24 nM) (Fig. 2A). The reduced affinity arises because kon (on-rate constant) and koff (off-rate constant) were ~5-fold lower and ~3-fold higher, respectively, for gl-PG16 (Fig. 2B). As the binding stoichiometry was also lower for gl-PG16 (Sm=0.4) than for mature PG16 (Sm=1.3) only a subset of the trimers can bind gl-PG16, perhaps because of variation in the presence or composition of nearby glycan sites (Fig. 2B). The difference in binding to BG505 SOSIP.664 between gl-PG16 and mature PG16 were more substantial in ELISA (EC50 values = 13.1 μg/ml and 0.031 μg/ml, respectively) than in SPR (Kd = 320 nM and 24 nM, respectively). This can probably be explained by the high off-rate, which results in loss of binding signal in ELISA during washing steps. We note that the BG505 trimers are based on a transmitter/founder virus sequence that is similar in the relevant regions to viruses isolated from the donor of PG9 and PG16 bNAbs (Hoffenberg et al., 2013)(Sanders et al., 2013). This sequence homology may help explain why gl-PG9 and gl-PG16 bind to the BG505 trimers. In contrast, but consistent with the ELISA data, gl-VRC01 did not bind to BG505 SOSIP.664-His trimers in the SPR assay (Fig. 2A).

Figure 2.

Figure 2

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Antibody binding to BG505 SOSIP.664 by SPR analysis A. Kinetic binding curves obtained by SPR and derived using the mature and gl- versions of PG16 and VRCO1, and chip-immobilized BG505 SOSIP.664-His trimers. B. Tabulated summary of the SPR analyses performed on BG505 SOSIP.664.

Gl-bNAb sequences are based on in silico predictions. Whether these inferred gl-bNAbs truly represent the in vivo naïve B cell receptors remains to be determined. Nevertheless, this exploratory study indicates that various SOSIP.664 trimers can bind to several gl-bNAbs, mainly ones that are directed to the V1/V2 loops. Hence these trimers are good starting points for engineering immunogens that more efficiently activate naïve B cell receptors and thereby initiate pathways that lead to the eventual emergence of bNAbs.

Acknowledgments

We thank Pia Dosenovic, Michel Nussenzweig, Larry Liao, Barton Haynes, Bill Schief, John Mascola and Peter Kwong for providing antibodies; Jean-Philippe Julien for providing the TPST1 plasmid; Steven de Taeye and Alba Torrents de la Peña for providing BG505, B41 and ZM197M SOSIP.664-D7324 trimers; and Ronald Derking and Marit van Gils for providing virus neutralization data.

Funding. MMR is a recipient of a fellowship from the Consejo Nacional de Ciencia y Tecnologıa (CONACyT) of Mexico. RWS is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (NWO) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011-280829-SHEV). This work was also supported by NIH grants P01 AI082362, P01 AI110657 and R37 AI36082 (JPM).

Contributor Information

Kwinten Sliepen, Email: k.h.sliepen@amc.uva.nl.

Max Medina-Ramírez, Email: j.m.medinaramirez@amc.uva.nl.

Anila Yasmeen, Email: yasmeenanila1@gmail.com.

John P. Moore, Email: jpm2003@med.cornell.edu.

Per Johan Klasse, Email: pek2003@med.cornell.edu.

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