Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity

Understanding pathways that promote HIV-1 broadly neutralizing antibody (bnAb) induction is crucial to advance bnAb-based vaccines. We recently demarcated host, viral, and disease parameters associated with bnAb development in a large HIV-1 cohort screen. By establishing comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13 HIV-1 antigens in 4,281 individuals in the same cohort, we now show that the same four parameters that are significantly linked with neutralization breadth, namely viral load, infection length, viral diversity, and ethnicity, also strongly influence HIV-1–binding antibody responses. However, the effects proved selective, shaping binding antibody responses in an antigen and IgG subclass–dependent manner. IgG response landscapes in bnAb inducers indicated a differentially regulated, IgG1-driven HIV-1 antigen response, and IgG1 binding of the BG505 SOSIP trimer proved the best predictor of HIV-1 neutralization breadth in plasma. Our findings emphasize the need to unravel immune modulators that underlie the differentially regulated IgG response in bnAb inducers to guide vaccine development.

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Development of a high-throughput bead based assay system to measure HIV-1 specific immune signatures in clinical samples

10.1101/195362 ◽

2017 ◽

Author(s):

Thomas Liechti ◽

Claus Kadelka ◽

Hanna Ebner ◽

Nikolas Friedrich ◽

Roger D. Kouyos ◽

...

Keyword(s):

High Throughput ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Assay System ◽

Clinical Samples ◽

Correlates Of Protection ◽

Technical Advances ◽

Broadly Neutralizing Antibody ◽

Binding Antibody ◽

Hiv 1

AbstractThe monitoring and assessment of a broadly neutralizing antibody (bnAb) based HIV-1 vaccine require detailed measurements of HIV-1 binding antibody responses to support the detection of correlates of protection. Here we describe the development of a flexible, high-throughput microsphere based multiplex assay system that allows monitoring complex binding antibody signatures. Studying a panel of 13 HIV-1 antigens in a parallel assessment of different IgG subclasses (IgG1, IgG2 and IgG3) we demonstrate the potential of our strategy. The technical advances we describe include means to improve antigen reactivity using directed neutravidin-biotin immobilization of antigens and biotin saturation to reduce background. A particular emphasis of our study was to provide tools for the assessment of reproducibility and stability of the assay system and strategies to control for variations allowing the application in high-throughput assays, where reliability of single measurements needs to be guaranteed.

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Immunogenicity, safety and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

10.1101/2020.03.06.980680 ◽

2020 ◽

Author(s):

Blasi Maria ◽

Negri Donatella ◽

Saunders O Kevin ◽

Baker J Erich ◽

Stadtler Hannah ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Lentiviral Vector ◽

Rhesus Macaques ◽

Infected Individual ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Safety And Efficacy ◽

Broadly Neutralizing Antibody ◽

Env Protein ◽

Hiv 1

AbstractA preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study we report the immunogenicity, safety and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Env induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/- protein immunizations using the same sequential envelopes. Compared to monkeys immunized with vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six month after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Our results show that while IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms, the use of non-stabilized sequential envelope trimers did not induce broadly neutralizing antibody responses.

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Lower Broadly Neutralizing Antibody Responses in Female Versus Male HIV-1 Infected Injecting Drug Users

Viruses ◽

10.3390/v11040384 ◽

2019 ◽

Vol 11 (4) ◽

pp. 384

Author(s):

Zelda EULER ◽

Tom L. VAN DEN KERKHOF ◽

Roger D. KOUYOS ◽

Damien C. TULLY ◽

Todd M. ALLEN ◽

...

Keyword(s):

Drug Users ◽

Natural Infection ◽

Neutralizing Antibody ◽

Injecting Drug Users ◽

Antibody Responses ◽

Multiple Factors ◽

Efficacy Trials ◽

Female Idus ◽

Broadly Neutralizing Antibody ◽

Hiv 1

Understanding the factors involved in the development of broadly neutralizing antibody (bNAb) responses in natural infection can guide vaccine design aimed at eliciting protective bNAb responses. Most of the studies to identify and study the development of bNAb responses have been performed in individuals who had become infected via homo- or heterosexual HIV-1 transmission; however, the prevalence and characteristics of bNAb responses in injecting drug users (IDUs) have been underrepresented. We retrospectively studied the prevalence of bNAb responses in HIV-1 infected individuals in the Amsterdam Cohort, including 50 male and 35 female participants who reported injecting drug use as the only risk factor. Our study revealed a significantly lower prevalence of bNAb responses in females compared to males. Gender, transmission route and CD4+ count at set point, but not viral load, were independently associated with the development of bNAb responses in IDUs. To further explore the influences of gender in the setting of IDU, we also looked into the Swiss 4.5k Screen. There we observed lower bNAb responses in female IDUs as well. These results reveal that the emergence of bNAbs may be dependent on multiple factors, including gender. Therefore, the effect of gender on the development of bNAb responses is a factor that should be taken into account when designing vaccine efficacy trials.

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Faculty Opinions recommendation of Co-administration of CH31 broadly neutralizing antibody does not affect development of vaccine-induced anti-HIV-1 envelope antibody responses in infant Rhesus macaques.

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

10.3410/f.734628033.793554775 ◽

2019 ◽

Author(s):

Antu Dey

Keyword(s):

Rhesus Macaques ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibody ◽

Anti Hiv ◽

Hiv 1 ◽

Infant Rhesus

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Development of a Norovirus P Particle Platform for Eliciting Neutralizing Antibody Responses to the Membrane Proximal External Region of Human Immunodeficiency Virus Type 1 Envelope

Protein and Peptide Letters ◽

10.2174/0929866521666140616120955 ◽

2014 ◽

Vol 21 (12) ◽

pp. 1230-1239

Author(s):

Yang Zang ◽

Jinpeng Bi ◽

Dongchuan Du ◽

Xintao Liu ◽

Yan Zhang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

External Region ◽

Membrane Proximal External Region ◽

Immunodeficiency Virus ◽

Hiv 1

Eliciting efficient broadly neutralizing antibodies (BnAbs) is an important goal that has yet to be achieved for human immunodeficiency type 1 (HIV-1) vaccine development, although they are rarely produced in virus-infected individuals. In particular, inducing specific neutralizing antibodies to the gp41 membrane proximal external region (MPER) has proven a difficult task. In this study, we introduce Norovirus P particles as a new platform to display the MPER epitope of HIV-1 as a vaccine with the aim of enhancing immune responses. The results showed that HIV-1 chimeric P particles were capable of inducing MPER-specific antibody responses in immunized guinea pigs, although only weakly neutralizing activity could be detected. These findings are consistent with other previous studies which have also focused on the well-studied 2F5 and 4E10 BnAbs. Our findings provide an alternate strategy for design of vaccines against HIV-1. However, great challenges remain in the effort to develop vaccines that can induce efficient HIV-1 neutralizing antibodies.

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Characterization of broadly neutralizing antibody responses to HIV-1 in a cohort of long term non-progressors

PLoS ONE ◽

10.1371/journal.pone.0193773 ◽

2018 ◽

Vol 13 (3) ◽

pp. e0193773 ◽

Cited By ~ 6

Author(s):

Nuria González ◽

Krisha McKee ◽

Rebecca M. Lynch ◽

Ivelin S. Georgiev ◽

Laura Jimenez ◽

...

Keyword(s):

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibody ◽

Hiv 1

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Tracing HIV-1 strains that imprint broadly neutralizing antibody responses

Nature ◽

10.1038/s41586-018-0517-0 ◽

2018 ◽

Vol 561 (7723) ◽

pp. 406-410 ◽

Cited By ~ 25

Author(s):

Roger D. Kouyos ◽

◽

Peter Rusert ◽

Claus Kadelka ◽

Michael Huber ◽

...

Keyword(s):

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibody ◽

Hiv 1

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A single mutation turns a non-binding germline-like predecessor of broadly neutralizing antibody into a binding antibody to HIV-1 envelope glycoproteins

mAbs ◽

10.4161/mabs.3.4.15740 ◽

2011 ◽

Vol 3 (4) ◽

pp. 402-407 ◽

Cited By ~ 5

Author(s):

Tingting Yuan ◽

Jingjing Li ◽

Mei-Yun Zhang

Keyword(s):

Neutralizing Antibody ◽

Envelope Glycoproteins ◽

Single Mutation ◽

Broadly Neutralizing Antibody ◽

Binding Antibody ◽

Hiv 1

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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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