Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

ABSTRACT Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies. IMPORTANCE Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.

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Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention

Annual Review of Immunology ◽

10.1146/annurev-immunol-080219-023629 ◽

2020 ◽

Vol 38 (1) ◽

pp. 673-703 ◽

Cited By ~ 12

Author(s):

Kathryn E. Stephenson ◽

Kshitij Wagh ◽

Bette Korber ◽

Dan H. Barouch

Keyword(s):

Clinical Trials ◽

Neutralizing Antibodies ◽

Passive Immunization ◽

Neutralizing Antibody ◽

Broadly Neutralizing Antibodies ◽

Aids Pandemic ◽

Broadly Neutralizing Antibody ◽

Early Phase Clinical Trials ◽

Hiv 1 ◽

Review Current

Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs.

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Cross-neutralization of SARS-CoV-2 by HIV-1 specific broadly neutralizing antibodies and polyclonal plasma

PLoS Pathogens ◽

10.1371/journal.ppat.1009958 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009958

Author(s):

Nitesh Mishra ◽

Sanjeev Kumar ◽

Swarandeep Singh ◽

Tanu Bansal ◽

Nishkarsh Jain ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Neutralizing Antibodies ◽

Cross Reactivity ◽

Type I ◽

Broadly Neutralizing Antibodies ◽

Human Monoclonal Antibodies ◽

Influenza Hemagglutinin ◽

Cd4 Binding Site ◽

Antigenic Profile ◽

Hiv 1

Cross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical features such as extensive somatic hypermutations, long complementary determining region (CDR) lengths, tyrosine sulfation and presence of insertions/deletions, enabling them to effectively neutralize diverse HIV-1 viruses despite extensive variations within the core epitopes they recognize. As some of the HIV-1 bnAbs have evolved to recognize the dense viral glycans and cross-reactive epitopes (CREs), we assessed if these bnAbs cross-react with SARS-CoV-2. Several HIV-1 bnAbs showed cross-reactivity with SARS-CoV-2 while one HIV-1 CD4 binding site bnAb, N6, neutralized SARS-CoV-2. Furthermore, neutralizing plasma antibodies of chronically HIV-1 infected children showed cross neutralizing activity against SARS-CoV-2 pseudoviruses. Collectively, our observations suggest that human monoclonal antibodies tolerating extensive epitope variability can be leveraged to neutralize pathogens with related antigenic profile.

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Broadly Neutralizing Antibodies for HIV-1 Prevention

Frontiers in Immunology ◽

10.3389/fimmu.2021.712122 ◽

2021 ◽

Vol 12 ◽

Author(s):

Stephen R. Walsh ◽

Michael S. Seaman

Keyword(s):

Neutralizing Antibodies ◽

Passive Immunization ◽

Lessons Learned ◽

Current Status ◽

Effective Vaccine ◽

Broadly Neutralizing Antibodies ◽

Efficacy Trials ◽

Cd4 Binding Site ◽

Preclinical Animal Models ◽

Hiv 1

Given the absence of an effective vaccine for protection against HIV-1 infection, passive immunization strategies that utilize potent broadly neutralizing antibodies (bnAbs) to block acquisition of HIV-1 are being rigorously pursued in the clinical setting. bnAbs have demonstrated robust protection in preclinical animal models, and several leading bnAb candidates have shown favorable safety and pharmacokinetic profiles when tested individually or in combinations in early phase human clinical trials. Furthermore, passive administration of bnAbs in HIV-1 infected individuals has resulted in prolonged suppression of viral rebound following interruption of combination antiretroviral therapy, and robust antiviral activity when administered to viremic individuals. Recent results from the first efficacy trials testing repeated intravenous administrations of the anti-CD4 binding site bnAb VRC01 have demonstrated positive proof of concept that bnAb passive immunization can confer protection against HIV-1 infection in humans, but have also highlighted the considerable barriers that remain for such strategies to effectively contribute to control of the epidemic. In this review, we discuss the current status of clinical studies evaluating bnAbs for HIV-1 prevention, highlight lessons learned from the recent Antibody Mediated Prevention (AMP) efficacy trials, and provide an overview of strategies being employed to improve the breadth, potency, and durability of antiviral protection.

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Griffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01084-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 1

Author(s):

Kathryn Fischer ◽

Kimberly Nguyen ◽

Patricia J. LiWang

Keyword(s):

Neutralizing Antibodies ◽

Glycosylation Site ◽

Significant Loss ◽

Broadly Neutralizing Antibodies ◽

Clade B ◽

Key Factor ◽

Clade C ◽

Cd4 Binding Site ◽

Gp120 Glycosylation ◽

Hiv 1

ABSTRACT Griffithsin (Grft) is an antiviral lectin that has been shown to potently inhibit HIV-1 by binding high-mannose N-linked glycosylation sites on HIV-1 gp120. A key factor for Grft potency is glycosylation at N295 of gp120, which is directly adjacent to N332, a target glycan for an entire class of broadly neutralizing antibodies (bNAbs). Here, we unify previous work on the importance of other glycans to Grft potency against HIV-1 and Grft’s role in mediating the conformational change of gp120 by mutating nearly every glycosylation site in gp120. In addition to a significant loss of Grft activity by the removal of glycosylation at N295, glycan absence at N332 or N448 was found to have moderate effects on Grft potency. Interestingly, in the absence of N295, Grft effectiveness could be improved by a mutation that results in the glycan at N448 shifting to N446, indicating that the importance of individual glycans may be related to their effect on glycosylation density. Grft’s ability to alter the structure of gp120, exposing the CD4 binding site, correlated with the presence of glycosylation at N295 only in clade B strains, not clade C strains. We further demonstrate that Grft can rescue the activity of the bNAbs PGT121 and PGT126 in the event of a loss or a shift of glycosylation at N332, where the bNAbs suffer a drastic loss of potency. Despite targeting the same region, Grft in combination with PGT121 and PGT126 produced additive effects. This indicates that Grft could be an important combinational therapeutic.

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Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein

Journal of Experimental Medicine ◽

10.1084/jem.20120423 ◽

2012 ◽

Vol 209 (8) ◽

pp. 1469-1479 ◽

Cited By ~ 123

Author(s):

Florian Klein ◽

Christian Gaebler ◽

Hugo Mouquet ◽

D. Noah Sather ◽

Clara Lehmann ◽

...

Keyword(s):

Binding Site ◽

Envelope Protein ◽

Neutralizing Antibodies ◽

Conformational Epitope ◽

Broadly Neutralizing Antibodies ◽

Cd4 Binding Site ◽

Capture Method ◽

Anti Hiv ◽

Hiv 1 ◽

Viral Isolates

Two to three years after infection, a fraction of HIV-1–infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti–HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti–HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti–HIV-1 serologic breadth and potency should not be limited to single epitopes.

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Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission

Journal of Experimental Medicine ◽

10.1084/jem.20131244 ◽

2013 ◽

Vol 210 (13) ◽

pp. 2813-2821 ◽

Cited By ~ 109

Author(s):

Marine Malbec ◽

Françoise Porrot ◽

Rejane Rua ◽

Joshua Horwitz ◽

Florian Klein ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Target Cells ◽

Type I ◽

Broadly Neutralizing Antibodies ◽

Major Mechanism ◽

Viral Spread ◽

Cell Transmission ◽

Cd4 Binding Site ◽

Virological Synapses ◽

Hiv 1

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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Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

Science ◽

10.1126/science.aan8630 ◽

2017 ◽

Vol 358 (6359) ◽

pp. 85-90 ◽

Cited By ~ 135

Author(s):

Ling Xu ◽

Amarendra Pegu ◽

Ercole Rao ◽

Nicole Doria-Rose ◽

Jochen Beninga ◽

...

Keyword(s):

Single Molecule ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Aids Vaccine ◽

Single Protein ◽

Hiv Antibodies ◽

Cd4 Binding Site ◽

Human Immunodeficiency Viruses ◽

Glycan Site ◽

Hiv 1

The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

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Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site

Journal of Virology ◽

10.1128/jvi.07139-11 ◽

2012 ◽

Vol 86 (10) ◽

pp. 5844-5856 ◽

Cited By ~ 60

Author(s):

X. Wu ◽

C. Wang ◽

S. O'Dell ◽

Y. Li ◽

B. F. Keele ◽

...

Keyword(s):

Binding Site ◽

Neutralizing Antibodies ◽

Selection Pressure ◽

Broadly Neutralizing Antibodies ◽

Cd4 Binding Site ◽

Hiv 1

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Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1

10.1101/2021.12.03.21267269 ◽

2021 ◽

Author(s):

Colin LaMont ◽

Jakub Otwinowski ◽

Kanika Vanshylla ◽

Henning Gruell ◽

Florian Klein ◽

...

Keyword(s):

Clinical Trials ◽

Neutralizing Antibodies ◽

Rational Design ◽

Sequence Data ◽

Viral Escape ◽

Broadly Neutralizing Antibodies ◽

Standing Variation ◽

Potential Alternative ◽

Pre Treatment ◽

Hiv 1

Broadly neutralizing antibodies (bNAbs) are promising targets for vaccination and therapy against HIV. Passive infusions of bNAbs have shown promise in clinical trials as a potential alternative for anti-retroviral therapy. A key challenge for the potential clinical application of bnAbs is the suppression of viral escape, which is more effectively achieved with a combination of bNAbs. However, identifying an optimal bNAb cocktail is combinatorially complex. Here, we propose a computational approach to predict the efficacy of a bNAb therapy trial based on the population genetics of HIV escape, which we parametrize using high-throughput HIV sequence data from a cohort of untreated bNAb-naive patients. By quantifying the mutational target size and the fitness cost of HIV-1 escape from bNAbs, we reliably predict the distribution of rebound times in three clinical trials. Importantly, we show that early rebounds are dominated by the pre-treatment standing variation of HIV-1 populations, rather than spontaneous mutations during treatment. Lastly, we show that a cocktail of three bNAbs is necessary to suppress the chances of viral escape below 1%, and we predict the optimal composition of such a bNAb cocktail. Our results offer a rational design for bNAb therapy against HIV-1, and more generally show how genetic data could be used to predict treatment outcomes and design new approaches to pathogenic control.

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