Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

Peña, Alba Torrents de la; Sanders, Rogier W.

doi:10.1186/s12977-018-0445-y

Cited by 36 publications

(32 citation statements)

References 103 publications

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“…A series of modifications over a multi-year period improve SOSIP trimer formation and stability, reduce exposure of non-NAb V3-and CD4i-epitopes and allow presentation on nanoparticles (21)(22)(23)(24)(25). Alternative trimer designs have also been reported (26)(27)(28)(29).…”

Section: Downloaded Frommentioning

confidence: 99%

Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Schorcht

Kerkhof

Cottrell

et al. 2020

J Virol

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The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1 infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Its structure at 4.3 Å resolution was overall similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous Tier-2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009 and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers. IMPORTANCE Elite neutralizers, i.e. individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.

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Section: Downloaded Frommentioning

confidence: 99%

Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Schorcht

Kerkhof

Cottrell

et al. 2020

J Virol

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“…For instance, the induction of MPER-specific bNAbs by vaccination has been especially difficult, largely due to the ambiguous structural information regarding native MPER conformation [72][73][74]. These findings have highlighted the importance of generating Env immunogens stabilized in different pre-fusion conformations, to allow for focused induction of neutralizing antibodies [75][76][77][78]. Some Env substitutions that stabilize the native gp160 trimer, with the goal of inducing neutralizing antibodies, have been enumerated by Torrents de la Peña A and Sanders RW [76].…”

Section: Plos Pathogensmentioning

confidence: 99%

Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein

et al. 2020

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The HIV-1 envelope glycoprotein (Env) mediates viral entry via conformational changes associated with binding the cell surface receptor (CD4) and coreceptor (CCR5/CXCR4), resulting in subsequent fusion of the viral and cellular membranes. While the gp120 Env surface subunit has been extensively studied for its role in viral entry and evasion of the host immune response, the gp41 transmembrane glycoprotein and its role in natural infection are less well characterized. Here, we identified a primary HIV-1 Env variant that consistently supports >300% increased viral infectivity in the presence of autologous or heterologous HIV-positive plasma. However, in the absence of HIV-positive plasma, viruses with this Env exhibited reduced infectivity that was not due to decreased CD4 binding. Using Env chimeras and sequence analysis, we mapped this phenotype to a change Q563R, in the gp41 heptad repeat 1 (HR1) region. We demonstrate that Q563R reduces viral infection by disrupting formation of the gp41 six-helix bundle required for virus-cell membrane fusion. Intriguingly, antibodies that bind cluster I epitopes on gp41 overcome this inhibitory effect, restoring infectivity to wild-type levels. We further demonstrate that the Q563R change increases HIV-1 sensitivity to broadly neutralizing antibodies (bNAbs) targeting the gp41 membrane-proximal external region (MPER). In summary, we identify an HIV-1 Env variant with impaired infectivity whose Env functionality is restored through the binding of host antibodies. These data contribute to our understanding of gp41 residues involved in membrane fusion and identify a mechanism by which host factors can alleviate a viral defect.

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“…A vaccine to prevent human immunodeficiency virus type 1 (HIV-1) infection will most likely need to induce potent and broad neutralizing antibodies (NAbs) that recognize the gp120 plus gp41 envelope glycoprotein trimer on the virion surface (1)(2)(3)(4)(5). The fragile virion-associated trimer can be appropriately mimicked for vaccine development by soluble recombinant SOSIP trimers that are stabilized by engineered sequence changes and produced in amounts sufficient for animal and human studies (3,4,6,7).…”

Section: Introductionmentioning

confidence: 99%

Neutralizing Antibody Induction by HIV-1 Envelope Glycoprotein SOSIP Trimers on Iron Oxide Nanoparticles May Be Impaired by Mannose Binding Lectin

Ringe

Portillo

Dosenovic

et al. 2020

J Virol

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We covalently attached human immunodeficiency virus type 1 (HIV-1) Env SOSIP trimers to iron oxide nanoparticles (IO-NPs) to create a particulate immunogen for neutralizing antibody (NAb) induction. The attached trimers, ∼20 per particle, retained native-like antigenicity, judged by reactivity with NAbs and non-NAbs. Bivalent (BG505 and B41) trimer IO-NPs were made, as were IO-NPs displaying B41 trimers carrying a PADRE T-cell helper epitope (TCHE). We immunized mice with B41 soluble or IO-NP trimers after PADRE peptide priming. After two immunizations, IO-NP presentation and the TCHE tag independently and substantially increased anti-trimer antibody responses, but titer differences waned after two further doses. Notable and unexpected findings were that autologous NAbs to the N289 glycan hole epitope were consistently induced in mice given soluble but not IO-NP trimers. Various recombinant mannose binding lectins (MBLs) and MBLs in sera of both murine and human origin bound to soluble and IO-NP trimers. MBL binding occluded the autologous NAb epitope on the B41 IO-NP trimers, which may contribute to its poor immunogenicity. The exposure of a subset of broadly active NAb epitopes was also impaired by MBL binding, which could have substantial implications for the utility of trimer-bearing nanoparticles in general and perhaps also for soluble Env proteins. IMPORTANCE Recombinant trimeric SOSIP proteins are vaccine components intended to induce neutralizing antibodies (NAbs) that prevent cells from infection by human immunodeficiency virus type 1 (HIV-1). A way to increase the strength of antibody responses to these proteins is to present them on the surface of nanoparticles (NPs). We chemically attached about 20 SOSIP trimers to NPs made of iron oxide (IO). The resulting IO-NP trimers had appropriate properties when we studied them in the laboratory but, unexpectedly, were less able to induce NAbs than nonattached trimers when used to immunize mice. We found that mannose binding lectins, proteins naturally present in the serum of mice and other animals, bound strongly to the soluble and IO-NP trimers, blocking access to antibody epitopes in a way that may impede the development of NAb responses. These findings should influence how trimer-bearing NPs of various designs are made and used.

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Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

Cited by 36 publications

References 103 publications

Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein

Neutralizing Antibody Induction by HIV-1 Envelope Glycoprotein SOSIP Trimers on Iron Oxide Nanoparticles May Be Impaired by Mannose Binding Lectin

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