Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization

Friedrich, Nikolas; Stiegeler, Emanuel; Glögl, Matthias; Lemmin, Thomas; Hansen, Simon; Kadelka, Claus; Wu, Yufan; Erñst, Patrick; Maliqi, Liridona; Foulkes, Caio; Morin, Mylène; Eroğlu, Mustafa; Liechti, Thomas; Ivan, Branislav; Reinberg, Thomas; Schaefer, Jonas V.; Karakus, Umut; Ursprung, Stephan; Mann, Axel; Rusert, Peter; Kouyos, Roger D.; Günthard, Huldrych F.; Plückthun, Andreas; Trkola, Alexandra

doi:10.1038/s41467-021-27075-0

Cited by 12 publications

(26 citation statements)

References 124 publications

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“…Neutralization of HIV-1, or any other viral pathogen, minimally requires an initial encounter with an Ab. The PG9, PG16, and PGT145 mAbs can efficiently neutralize REJO virus (83), thus lack of detectable binding was unexpected, particularly since V3 is shielded only when the native Env trimer is in the closed pre-fusion conformation: a conformation that is required for the binding of V2q mAbs (99, 113).…”

Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Antibody Epitopes on HIV-1 Particles are exposed after Virus Interaction with Host Cells

Rao

Lambert

Upadhyay

2023

Preprint

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HIV-1 envelope glycoproteins (Env) are critical for infection and are key targets for vaccine development. Env proteins displayed on virions are conformationally diverse, comprising both functional and non-functional forms. These heterogeneous Env populations have important implications for neutralizing and non-neutralizing antibody elicitation and functions. This study aimed to interrogate the antigenic composition of Env on virions. Using a flow cytometry-based assay we show that only some epitopes including V2i, gp120-g41 interface, and gp41-MPER are accessible on HIV-1 particles, while V3, V2q, and select CD4bs epitopes are obscured for monoclonal antibody (mAb) binding. To investigate the mechanisms contributing to the masking of these epitopes we first asked whether time-dependent dynamics of Env can affect their exposure. Extending the time of virus-mAb interaction increased the binding of mAbs, epitopes of which were already accessible on virions but not those that are occluded. However, the occluded epitopes became accessible after conformational unmasking was induced by pre-binding of select mAbs, prompting us to test if similar conformational changes are required for these mAbs to exhibit their neutralization capability. We tested HIV-1 neutralization where virus-mAb mix was incubated or not incubated for one-hour prior to adding the target cells. Similar levels of neutralization were observed under both assay conditions, suggesting that interaction between virus and cells sensitizes the virions for neutralization via broadly-neutralizing antibodies (bNAbs). These findings provide insight into how bNAbs may gain access to these occluded epitopes to exert their neutralization effects. Further studies with larger virus and mAb panels are warranted.

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Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Antibody Epitopes on HIV-1 Particles are exposed after Virus Interaction with Host Cells

Rao

Lambert

Upadhyay

2023

Preprint

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“…Research indicated that long and highly glycosylated V1 regions shield HIV-1 from recognition by V3-directed bNAbs ( Silver et al., 2019 ). V3-crown antibodies show exceptional potency and cross-reactivity in the absence of V1V2 shielding, indicating that distinct conformations of the HIV-1 V3 loop crown can be targeted for broad neutralization ( Friedrich et al., 2021 ). Fewer, or deletion of, PNGS in V1V2 suggested that the V3 loop may be selectively exposed and accessible on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

Wang

Liang

Huang

et al. 2022

Front. Cell. Infect. Microbiol.

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The diversity of HIV-1 envelope (Env) glycoproteins affects the potency and breadth of broadly neutralizing antibodies (bNAbs), a promising alternative to antiretroviral drugs for the prevention and treatment of HIV-1 infection. To facilitate immunogen design and development of therapeutic neutralizing antibodies, we characterized viral evolution and monitored the changes in neutralizing activity/sensitivity of a long-term non-progressor patient with HIV-1 CRF07_BC infection. Fifty-nine full-length Env gene fragments were derived from four plasma samples sequentially harvested from the patient between 2016 and 2020. Sequencing of patient-derived Env genes revealed that potential N-linked glycosylation sites (PNGS) in V1 and V5 significantly increased over time. Further, 24 functional Env-pseudotyped viruses were generated based on Env gene sequences. While all 24 Env-pseudotyped viruses remained sensitive to concurrent and subsequent autologous plasma, as well as bNAbs, including 10E8, VRC01, and 12A21, Env-pseudotyped viruses corresponding to later sampling time were increasingly more resistant to autologous plasma and bNAbs. All 24 Env-pseudotyped viruses were resistant to bNAbs 2G12, PGT121, and PGT135. The neutralization breadth of plasma from all four sequential samples was 100% against the global HIV-1 reference panel. Immune escape mutants resulted in increased resistance to bNAb targeting of different epitopes. Our study identified known mutations F277W in gp41 and previously uncharacterized mutation S465T in V5 which may be associated with increased viral resistance to bNAbs.

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“…DARPins directed against the hetero-oligomeric macromolecular multiprotein complex, which comprises part of the baseplate of the phage could inhibit TP901-1 infection. Furthermore, the DARPin technology was employed to design HIV inhibitors targeting the envelope glycoprotein gp120 [ 72 , 73 ]. Broad neutralization could be achieved by a DARPin molecule directed to the V3 crown of HIV envelope glycoprotein gp120, providing relevant information for the development of novel antiviral strategies against HIV.…”

Section: Viral Applicationsmentioning

confidence: 99%

Designed Ankyrin Repeat Proteins: A New Class of Viral Entry Inhibitors

Walser

Mayor

Rothenberger

2022

Viruses

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Designed ankyrin repeat proteins (DARPins) are engineered proteins comprising consensus designed ankyrin repeats as scaffold. Tightly packed repeats form a continuous hydrophobic core and a large groove-like solvent-accessible surface that creates a binding surface. DARPin domains recognizing a target of interest with high specificity and affinity can be generated using a synthetic combinatorial library and in vitro selection methods. They can be linked together in a single molecule to build multispecific and multifunctional proteins without affecting expression or function. The modular architecture of DARPins offers unprecedented possibilities of design and opens avenues for innovative antiviral strategies.

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Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization

Cited by 12 publications

References 124 publications

Broadly Neutralizing Antibody Epitopes on HIV-1 Particles are exposed after Virus Interaction with Host Cells

Broadly Neutralizing Antibody Epitopes on HIV-1 Particles are exposed after Virus Interaction with Host Cells

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

Designed Ankyrin Repeat Proteins: A New Class of Viral Entry Inhibitors

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