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

ABSTRACT To minimize immune responses against infected cells, HIV-1 limits the surface expression of its envelope glycoprotein (Env). Here, we demonstrate that this mechanism is specific for the Env conformation and affects the efficiency of antibody-dependent cellular cytotoxicity (ADCC). Using flow cytometry and confocal microscopy, we show that broadly neutralizing antibodies (bNAbs) targeting the “closed” conformation of Env induce its internalization from the surface. In contrast, non-neutralizing antibodies (nNAbs) are displayed on the cell surface for prolonged period of times. The bNAb-induced Env internalization can be decreased by blocking dynamin function, which translates into higher susceptibilities of infected cells to ADCC. Our results suggest that antibody-mediated Env internalization is a mechanism used by HIV-1 to evade immune responses against the “closed” conformation of Env expressed on HIV-1-infected cells. IMPORTANCE HIV-1 has evolved to acquire several strategies to limit the exposure of its envelope glycoproteins (Env) on the surface of infected cells. In this study, we show that antibody-induced Env internalization is conformation specific and reduces the susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). Thus, a better understanding of this mechanism might help develop antibodies with improved capacities to mediate ADCC.

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Expression of HIV-1 broadly neutralizing antibodies mediated by recombinant adeno-associated virus 8 in vitro and in vivo

Molecular Immunology ◽

10.1016/j.molimm.2016.10.011 ◽

2016 ◽

Vol 80 ◽

pp. 68-77

Author(s):

Yongjiao Yu ◽

Lu Fu ◽

Xiaoyu Jiang ◽

Shanshan Guan ◽

Ziyu Kuai ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Adeno Associated Virus ◽

Hiv 1

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HIV-1 Envelope Glycoprotein Cell Surface Localization Is Associated with Antibody-Induced Internalization

Viruses ◽

10.3390/v13101953 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1953

Author(s):

Sai Priya Anand ◽

Jérémie Prévost ◽

Jade Descôteaux-Dinelle ◽

Jonathan Richard ◽

Dung N. Nguyen ◽

...

Keyword(s):

Cell Surface ◽

Neutralizing Antibodies ◽

Surface Expression ◽

Broadly Neutralizing Antibodies ◽

Open Conformation ◽

Surface Localization ◽

Infected Cells ◽

Cell Surface Localization ◽

Underlying Mechanisms ◽

Hiv 1

To minimize immune responses against infected cells, HIV-1 has evolved different mechanisms to limit the surface expression of its envelope glycoproteins (Env). Recent observations suggest that the binding of certain broadly neutralizing antibodies (bNAbs) targeting the ‘closed’ conformation of Env induces its internalization. On the other hand, non-neutralizing antibodies (nNAbs) that preferentially target Env in its ‘open’ conformation, remain bound to Env on the cell surface for longer periods of time. In this study, we attempt to better understand the underlying mechanisms behind the differential rates of antibody-mediated Env internalization. We demonstrate that ‘forcing’ open Env using CD4 mimetics allows for nNAb binding and results in similar rates of Env internalization as those observed upon the bNAb binding. Moreover, we can identify distinct populations of Env that are differentially targeted by Abs that mediate faster rates of internalization, suggesting that the mechanism of antibody-induced Env internalization partially depends on the localization of Env on the cell surface.

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Effect of HIV-1 Env on SERINC5 Antagonism

Journal of Virology ◽

10.1128/jvi.02214-16 ◽

2016 ◽

Vol 91 (4) ◽

Cited By ~ 45

Author(s):

Saina Beitari ◽

Shilei Ding ◽

Qinghua Pan ◽

Andrés Finzi ◽

Chen Liang

Keyword(s):

Antiviral Activity ◽

High Frequency ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Viral Loads ◽

Virion Incorporation ◽

Viral Particles ◽

Ccr5 Inhibitor ◽

Hiv 1

ABSTRACT SERINC5 is able to restrict HIV-1 infection by drastically impairing the infectivity of viral particles. Studies have shown that the HIV-1 Nef protein counters SERINC5 through downregulating SERINC5 from the cell surface and preventing the virion incorporation of SERINC5. In addition, the Env proteins of some HIV-1 strains can also overcome SERINC5 inhibition. However, it is unclear how HIV-1 Env does so and why HIV-1 has two mechanisms to resist SERINC5 inhibition. The results of this study show that neither Env nor Nef prevents high levels of ectopic SERINC5 from being incorporated into HIV-1 particles, except that Env, but not Nef, is able to resist inhibition by virion-associated SERINC5. Testing of a panel of HIV-1 Env proteins from different subtypes revealed a high frequency of SERINC5-resistant Envs. Interestingly, although the SERINC5-bearing viruses were not inhibited by SERINC5 itself, they became more sensitive to the CCR5 inhibitor maraviroc and some neutralizing antibodies than the SERINC5-free viruses, which suggests a possible influence of SERINC5 on Env function. We conclude that HIV-1 Env is able to overcome SERINC5 without preventing SERINC5 virion incorporation. IMPORTANCE HIV-1 Nef is known to enhance the infectivity of HIV-1 particles and to contribute to the maintenance of high viral loads in patients. However, the underlying molecular mechanism remained elusive until the recent discovery of the antiviral activity of SERINC5. SERINC5 profoundly inhibits HIV-1 but is antagonized by Nef, which prevents the incorporation of SERINC5 into viral particles. Here, we show that HIV-1 Env, but not Nef, is able to resist high levels of SERINC5 without excluding SERINC5 from incorporation into viral particles. However, the virion-associated SERINC5 renders HIV-1 more sensitive to some broadly neutralizing antibodies. It is possible that, under the pressure of some neutralizing antibodies in vivo, HIV-1 needs Nef to remove SERINC5 from viral particles, even though viral Env is able to resist virion-associated SERINC5.

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New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

Journal of Virology ◽

10.1128/jvi.00149-17 ◽

2017 ◽

Vol 91 (9) ◽

Cited By ~ 2

Author(s):

S. Abigail Smith ◽

Cynthia A. Derdeyn

Keyword(s):

Neutralizing Antibodies ◽

Differential Susceptibility ◽

Neutralizing Antibody ◽

Dependent Manner ◽

Broadly Neutralizing Antibodies ◽

Cell Infection ◽

Viral Spread ◽

Broadly Neutralizing Antibody ◽

Hiv 1

ABSTRACT HIV-1 infection from cell-to-cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al. (H. Li, C. Zony, P. Chen, and B. K. Chen, J. Virol. 91:e02425-16, 2017, https://doi.org/10.1128/JVI.02425-16 ) showed that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell-to-cell infection in a context-dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.

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Potent In Vivo NK Cell-Mediated Elimination of HIV-1-Infected Cells Mobilized by a gp120-Bispecific and Hexavalent Broadly Neutralizing Fusion Protein

Journal of Virology ◽

10.1128/jvi.00937-17 ◽

2017 ◽

Vol 91 (20) ◽

Cited By ~ 18

Author(s):

Ariola Bardhi ◽

Yanling Wu ◽

Weizao Chen ◽

Wei Li ◽

Zhongyu Zhu ◽

...

Keyword(s):

Fusion Protein ◽

Neutralizing Antibodies ◽

Nk Cell ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

Infected Cells ◽

Latent Hiv ◽

Shiv Infection ◽

Hiv 1

ABSTRACT Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including in vivo neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate in vivo human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. IMPORTANCE Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and SHIV infection in humanized mouse and macaque models, respectively, including in vivo neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir.

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Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

10.1101/2020.02.14.940395 ◽

2020 ◽

Author(s):

Ananya Saha ◽

Narendra M. Dixit

Keyword(s):

Neutralizing Antibodies ◽

Latent Reservoir ◽

Broadly Neutralizing Antibodies ◽

Art Initiation ◽

Latently Infected ◽

Infected Cells ◽

Resistant Strains ◽

Maintenance Of Remission ◽

Hiv 1

AbstractBroadly neutralizing antibodies (bNAbs) of HIV-1 hold promise of eliciting long-term HIV-1 remission. Surprisingly, the bNAb VRC01, when administered concomitantly with the cessation of successful antiretroviral therapy (ART), failed rapidly in chronic HIV-1 patients. We hypothesized that the failure was due to VRC01-resistant strains that were formed before ART initiation, survived ART in latently infected cells, and were reactivated during VRC01 therapy. Current assay limitations preclude testing this hypothesis experimentally. We developed a mathematical model based on the hypothesis and challenged it with available clinical data. The model integrated within-host HIV-1 evolution, stochastic latency reactivation and viral dynamics with multiple dose VRC01 pharmacokinetics. With a virtual patient population, model predictions quantitatively captured data from two independent clinical trials. Accordingly, we attributed VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral recrudescence, particularly during trough VRC01 levels. Accounting for pre-existing resistance may help bNAb therapies maximize HIV-1 remission.

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Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104651118 ◽

2021 ◽

Vol 118 (30) ◽

pp. e2104651118

Author(s):

Matthijs Meijers ◽

Kanika Vanshylla ◽

Henning Gruell ◽

Florian Klein ◽

Michael Lässig

Keyword(s):

Viral Load ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Broadly Neutralizing Antibodies ◽

Antibody Treatment ◽

Trade Off ◽

Escape Dynamics ◽

Resistance Evolution ◽

Hiv 1

Broadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map a fitness model of HIV-1 interacting with broadly neutralizing antibodies using in vivo data from a recent clinical trial. We identify two fitness factors, antibody dosage and viral load, that determine viral reproduction rates reproducibly across different hosts. The model successfully predicts the escape dynamics of HIV-1 in the course of an antibody treatment, including a characteristic frequency turnover between sensitive and resistant strains. This turnover is governed by a dosage-dependent fitness ranking, resulting from an evolutionary trade-off between antibody resistance and its collateral cost in drug-free growth. Our analysis suggests resistance–cost trade-off curves as a measure of antibody performance in the presence of resistance evolution.

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