Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission?

Many broadly neutralizing antibodies (bnAbs) targeting the HIV-1 envelope glycoprotein are being assessed in clinical trials as strategies for HIV-1 prevention, treatment, and antiretroviral-free remission. BnAbs can neutralize HIV-1 and target infected cells for elimination. Concerns about HIV-1 resistance to single bnAbs have led to studies of bnAb combinations with non-overlapping resistance profiles. This review focuses on the potential for bnAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines or other novel therapeutics. Key topics include preliminary activity of bnAbs in preclinical models and in human studies of HIV-1 remission, clinical trial designs, and antibody design strategies to optimize pharmacokinetics, coverage of rebound-competent virus, and enhancement of cellular immune functions.

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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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Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo

Science ◽

10.1126/science.aaf1279 ◽

2016 ◽

Vol 352 (6288) ◽

pp. 1001-1004 ◽

Cited By ~ 185

Author(s):

C.-L. Lu ◽

D. K. Murakowski ◽

S. Bournazos ◽

T. Schoofs ◽

D. Sarkar ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Infected Cells ◽

Hiv 1

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Antibody-Induced Internalization of HIV-1 Env Proteins Limits Surface Expression of the Closed Conformation of Env

Journal of Virology ◽

10.1128/jvi.00293-19 ◽

2019 ◽

Vol 93 (11) ◽

Cited By ~ 10

Author(s):

Sai Priya Anand ◽

Jonathan R. Grover ◽

William D. Tolbert ◽

Jérémie Prévost ◽

Jonathan Richard ◽

...

Keyword(s):

Immune Responses ◽

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Surface Expression ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Broadly Neutralizing Antibodies ◽

Closed Conformation ◽

Infected Cells ◽

Hiv 1

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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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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Plant-made HIV vaccines and potential candidates

10.31221/osf.io/2d6qk ◽

2020 ◽

Author(s):

Jocelyne Tremouillaux-Guiller ◽

Khaled Moustafa ◽

Kathleen Hefferon ◽

Goabaone Gaobotse ◽

Abdullah Makhzoum

Keyword(s):

Neutralizing Antibodies ◽

Opportunistic Infections ◽

Broadly Neutralizing Antibodies ◽

Hiv Vaccines ◽

Therapeutic Vaccines ◽

Hiv Therapy ◽

The Past ◽

Health Burdens ◽

Anti Hiv ◽

Hiv 1

Millions of people around the world suffer from heavy social and health burdens related to HIV/AIDS and its associated opportunistic infections. To reduce these burdens, preventive and therapeutic vaccines are required. Effective HIV vaccines have been under investigation for several decades using different animal models. Potential plant-made HIV vaccine candidates have also gained attention in the past few years. In addition to this, broadly neutralizing antibodies produced in plants which can target conserved viral epitopes and neutralize mutating HIV strains have been identified. Numerous epitopes of glycoproteins and capsid proteins of HIV-1 are a part of HIV therapy. Here, we discuss some recent findings aiming to produce anti-HIV-1 recombinant proteins in engineered plants for AIDS prophylactics and therapeutic treatments.

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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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Lack of ADCC Breadth of Human Nonneutralizing Anti-HIV-1 Antibodies

Journal of Virology ◽

10.1128/jvi.02440-16 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 36

Author(s):

Timothée Bruel ◽

Florence Guivel-Benhassine ◽

Valérie Lorin ◽

Hugues Lortat-Jacob ◽

Françoise Baleux ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Hiv Positive ◽

Antibody Dependent Cellular Cytotoxicity ◽

Broadly Neutralizing Antibodies ◽

Efficacy Trial ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Anti Hiv ◽

Hiv 1 ◽

Rv144 Vaccine

ABSTRACT Anti-human immunodeficiency virus type 1 (HIV-1) nonneutralizing antibodies (nnAbs) capable of antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. Broadly neutralizing antibodies (bNAbs) also mediate ADCC in cell culture and rely on their Fc region for optimal efficacy in animal models. Here, we selected 9 monoclonal nnAbs and 5 potent bNAbs targeting various epitopes and conformations of the gp120/41 complex and analyzed the potency of the two types of antibodies to bind and eliminate HIV-1-infected cells in culture. Regardless of their neutralizing activity, most of the selected antibodies recognized and killed cells infected with two laboratory-adapted HIV-1 strains. Some nnAbs also bound bystander cells that may have captured viral proteins. However, in contrast to the bNAbs, the nnAbs bound poorly to reactivated infected cells from 8 HIV-positive individuals and did not mediate effective ADCC against these cells. The nnAbs also inefficiently recognize cells infected with 8 different transmitted-founder (T/F) isolates. The addition of a synthetic CD4 mimetic enhanced the binding and killing efficacy of some of the nnAbs in an epitope-dependent manner without reaching the levels achieved by the most potent bNAbs. Overall, our data reveal important qualitative and quantitative differences between nnAbs and bNAbs in their ADCC capacity and strongly suggest that the breadth of recognition of HIV-1 by nnAbs is narrow. IMPORTANCE Most of the anti-HIV antibodies generated by infected individuals do not display potent neutralizing activities. These nonneutralizing antibodies (nnAbs) with antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. However, in primate models, the nnAbs do not protect against simian-human immunodeficiency virus (SHIV) acquisition. Thus, the role of nnAbs with ADCC activity in protection from infection remains debatable. In contrast, broadly neutralizing antibodies (bNAbs) neutralize a large array of viral strains and mediate ADCC in cell culture. We analyzed the capacities of 9 nnAbs and 5 bNAbs to eliminate infected cells. We selected 18 HIV-1 strains, including virus reactivated from the reservoir of HIV-positive individuals and transmitted-founder isolates. We report that the nnAbs bind poorly to cells infected with primary HIV-1 strains and do not mediate potent ADCC. Overall, our data show that the breadth of recognition of HIV-1 by nnAbs is narrow.

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