HIV-1 cell-to-cell transmission and broadly neutralizing antibodies

The neutralizing activity of anti–HIV-1 antibodies is typically measured in assays where cell-free virions enter reporter cell lines. However, HIV-1 cell to cell transmission is a major mechanism of viral spread, and the effect of the recently described broadly neutralizing antibodies (bNAbs) on this mode of transmission remains unknown. Here we identify a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes. These antibodies target either the CD4-binding site (NIH45-46 and 3BNC60) or the glycan/V3 loop (10-1074 and PGT121) on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. These antibodies accumulate at virological synapses and impair the clustering and fusion of infected and target cells and the transfer of viral material to uninfected T cells. In addition, they block viral cell to cell transmission to plasmacytoid DCs and thereby interfere with type-I IFN production. Thus, only a subset of bNAbs can efficiently prevent HIV-1 cell to cell transmission, and this property should be considered an important characteristic defining antibody potency for therapeutic or prophylactic antiviral strategies.

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Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

Journal of Virology ◽

10.1128/jvi.02425-16 ◽

2017 ◽

Vol 91 (9) ◽

Cited By ~ 29

Author(s):

Hongru Li ◽

Chati Zony ◽

Ping Chen ◽

Benjamin K. Chen

Keyword(s):

Neutralizing Antibodies ◽

Wide Spectrum ◽

Free Form ◽

Broadly Neutralizing Antibodies ◽

Free Virus ◽

Cell Infection ◽

Neutralization Capacity ◽

Cell Transmission ◽

Sorting Motif ◽

Hiv 1

ABSTRACT Broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1 patients and can potently block infection of a wide spectrum of HIV-1 subtypes. These antibodies define common epitopes shared by many viral isolates. While bNAbs potently antagonize infection with cell-free virus, inhibition of HIV-1 transmission from infected to uninfected CD4+ T cells through virological synapses (VS) has been found to require greater amounts of antibody. In this study, we examined two well-studied molecular clones and two transmitted/founder (T/F) clones for their sensitivities to a panel of bNAbs in cell-free and cell-to-cell infection assays. We observed resistance of cell-to-cell transmission to antibody neutralization that was reflected not only by reductions of antibody potency but also by decreases in maximum neutralization capacity relative to the levels seen with cell-free infections. BNAbs targeting different epitopes exhibited incomplete neutralization against cell-associated virus with T/F Envs, which was not observed with the cell-free form of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif as a determinant that can affect the incomplete neutralization of these T/F clones in cell-to-cell infection. These findings indicate that the signal that affects surface expression and/or internalization of Env from the plasma membrane can modulate the presentation of neutralizing epitopes on infected cells. These results highlight that a fraction of virus can escape from high concentrations of antibody through cell-to-cell infection while remaining sensitive to neutralization in cell-free infection. The ability to fully inhibit cell-to-cell transmission may represent an important consideration in the development of antibodies for treatment or prophylaxis. IMPORTANCE In recent years, isolation of new-generation HIV-1 bNAbs has invigorated HIV vaccine research. These bNAbs display remarkable potency and breadth of coverage against cell-free virus; however, they exhibit a diminished ability to block HIV-1 cell-to-cell transmission. The mechanism(s) by which HIV-1 resists neutralization when transmitting through VS remains uncertain. We examined a panel of bNAbs for their ability to neutralize HIV-1 T/F viruses in cell-to-cell infection assays. We found that some antibodies exhibit not only reduced potency but also decreased maximum neutralization capacity or in vitro efficacy against cell-to-cell infection of HIV-1 with T/F Envs compared to cell-free infection of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif YXXL as a determinant that can affect the incomplete neutralization phenotype of these T/F clones. When the maximum neutralization capacity falls short of 100%, this can have a major impact on the ability of antibodies to halt viral replication.

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Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent

PLoS Pathogens ◽

10.1371/journal.ppat.1004966 ◽

2015 ◽

Vol 11 (7) ◽

pp. e1004966 ◽

Cited By ~ 41

Author(s):

Lucia Reh ◽

Carsten Magnus ◽

Merle Schanz ◽

Jacqueline Weber ◽

Therese Uhr ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Cell Transmission ◽

Hiv 1 ◽

Is Strain ◽

Cell Cell

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Broadly Neutralizing Antibodies (BNAbs): templates for HIV-1 vaccine design

Journal of Medical Discovery ◽

10.24262/jmd.2.4.17039 ◽

2017 ◽

Vol 2 (4) ◽

Cited By ~ 1

Author(s):

Lixin Yan ◽

◽

Lihong Liu ◽

Yilin Wang ◽

Xi Huang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Design ◽

Broadly Neutralizing Antibodies ◽

Hiv 1

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Faculty Opinions recommendation of Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726369545.793518839 ◽

2016 ◽

Author(s):

Stephen J Kent

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Infected Cells ◽

Hiv 1

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Faculty Opinions recommendation of Elimination of HIV-1-infected cells by broadly neutralizing antibodies.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726190699.793517949 ◽

2016 ◽

Author(s):

Boris Matija Peterlin

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Infected Cells ◽

Hiv 1

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A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

Scientific Reports ◽

10.1038/s41598-021-84116-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jean-François Bruxelle ◽

Tess Kirilenko ◽

Nino Trattnig ◽

Yiqiu Yang ◽

Matteo Cattin ◽

...

Keyword(s):

Transgenic Mice ◽

Envelope Protein ◽

Protein Sequence ◽

Neutralizing Antibodies ◽

Human Antibody ◽

Broadly Neutralizing Antibodies ◽

Specific Antibodies ◽

Strong Binding ◽

Hiv Envelope ◽

Hiv 1

AbstractThe occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by inferred germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

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HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽

10.3390/v13050852 ◽

2021 ◽

Vol 13 (5) ◽

pp. 852

Author(s):

Ashley Lauren Bennett ◽

Rory Henderson

Keyword(s):

Host Cell ◽

Conformational Changes ◽

Neutralizing Antibodies ◽

Critical Role ◽

Cell Receptor ◽

Broadly Neutralizing Antibodies ◽

Structural Mapping ◽

Host Cell Receptor ◽

Immunogen Design ◽

Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

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Embracing diversity: how can broadly neutralizing antibodies effectively target a diverse HIV-1 reservoir?

Current Opinion in Pharmacology ◽

10.1016/j.coph.2020.10.004 ◽

2020 ◽

Vol 54 ◽

pp. 173-178

Author(s):

Andrew Wilson ◽

Rebecca M Lynch

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Hiv 1

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A Coreceptor-Mimetic Peptide Enhances the Potency of V3-Glycan Antibodies

Journal of Virology ◽

10.1128/jvi.01653-18 ◽

2018 ◽

Vol 93 (5) ◽

Author(s):

Ina Fetzer ◽

Meredith E. Davis-Gardner ◽

Matthew R. Gardner ◽

Barnett Alfant ◽

Jesse A. Weber ◽

...

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Target Cells ◽

Broadly Neutralizing Antibodies ◽

Mimetic Peptide ◽

Heavy Chains ◽

Binding Domains ◽

C Terminus ◽

Gp120 Subunit ◽

Hiv 1

ABSTRACTBroadly neutralizing antibodies (bNAbs) target five major epitopes on the HIV-1 envelope glycoprotein (Env). The most potent bNAbs have median half-maximal inhibitory concentration (IC50) values in the nanomolar range, and the broadest bNAbs neutralize up to 98% of HIV-1 strains. The engineered HIV-1 entry inhibitor eCD4-Ig has greater breadth than bNAbs and similar potency. eCD4-Ig is markedly more potent than CD4-Ig due to its C-terminal coreceptor-mimetic peptide. Here we investigated whether the coreceptor-mimetic peptide mim6 improved the potency of bNAbs with different epitopes. We observed that when mim6 was appended to the C terminus of the heavy chains of bNAbs, this sulfopeptide improved the potency of all classes of bNAbs against HIV-1 isolates that are sensitive to neutralization by the sulfopeptide alone. However, mim6 did not significantly enhance neutralization of other isolates when appended to most classes of bNAbs, with one exception. Specifically, mim6 improved the potency of bNAbs of the V3-glycan class, including PGT121, PGT122, PGT128, and 10-1074, by an average of 2-fold for all HIV-1 isolates assayed. Despite this difference, 10-1074 does not induce exposure of the coreceptor-binding site, and addition of mim6 to 10-1074 did not promote shedding of the gp120 subunit of Env. Mixtures of 10-1074 and an Fc domain fused to mim6 neutralized less efficiently than a 10-1074/mim6 fusion, indicating that mim6 enhances the avidity of this fusion. Our data show that mim6 can consistently improve the potency of V3-glycan antibodies and suggest that these antibodies bind in an orientation that facilitates mim6 association with Env.IMPORTANCEHIV-1 requires both the cellular receptor CD4 and a tyrosine-sulfated coreceptor to infect its target cells. CD4-Ig is a fusion of the HIV-1-binding domains of CD4 with an antibody Fc domain. Previous studies have demonstrated that the potency of CD4-Ig is markedly increased by appending a coreceptor-mimetic sulfopeptide to its C terminus. We investigated whether this coreceptor-mimetic peptide improves the potency of broadly neutralizing antibodies (bNAbs) targeting five major epitopes on the HIV-1 envelope glycoprotein (Env). We observed that inclusion of the sulfopeptide dramatically improved the potency of all bNAb classes against isolates with more-open Env structures, typically those that utilize the coreceptor CXCR4. In contrast, the sulfopeptide improved only V3-glycan antibodies when neutralizing primary isolates, on average by 2-fold. These studies improve the potency of one class of bNAbs, show that coreceptor-mimetic sulfopeptides enhance neutralization through distinct mechanisms, and provide insight for the design of novel multispecific entry inhibitors.

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