Multiscale affinity maturation simulations to elicit HIV broadly neutralizing antibodies

The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.

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Host-pathogen coevolution and the emergence of broadly neutralizing antibodies in chronic infections

10.1101/034959 ◽

2015 ◽

Author(s):

Armita Nourmohammad ◽

Jakub Otwinowski ◽

Joshua B Plotkin

Keyword(s):

Immune System ◽

Neutralizing Antibodies ◽

Adaptive Immune System ◽

Analytical Framework ◽

Mathematical Framework ◽

Broadly Neutralizing Antibodies ◽

Chronic Infections ◽

Adaptive Immune ◽

Immune Parameters ◽

Genotype Frequencies

The vertebrate adaptive immune system provides a flexible and diverse set of molecules to neutralize pathogens. Yet, viruses such as HIV can cause chronic infections by evolving as quickly as the adaptive immune system, forming an evolutionary arms race. Here we introduce a mathematical framework to study the coevolutionary dynamics of antibodies with antigens within a host. We focus on changes in the binding interactions between the antibody and antigen populations, which result from the underlying stochastic evolution of genotype frequencies driven by mutation, selection, and drift. We identify the critical viral and immune parameters that determine the distribution of antibody-antigen binding affinities. We also identify definitive signatures of coevolution that measure the reciprocal response between antibodies and viruses, and we introduce experimentally measurable quantities that quantify the extent of adaptation during continual coevolution of the two opposing populations. Using this analytical framework, we infer rates of viral and immune adaptation based on time-shifted neutralization assays in two HIV-infected patients. Finally, we analyze competition between clonal lineages of antibodies and characterize the fate of a given lineage in terms of the state of the antibody and viral populations. In particular, we derive the conditions that favor the emergence of broadly neutralizing antibodies, which may be useful in designing a vaccine against HIV.

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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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Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen binding affinity

10.1101/275438 ◽

2018 ◽

Author(s):

Pia Dosenovic ◽

Ervin E. Kara ◽

Anna-Klara Pettersson ◽

Andrew McGuire ◽

Matthew Gray ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Neutralizing Antibodies ◽

Cell Receptor ◽

Broadly Neutralizing Antibodies ◽

Precursor Frequency ◽

The Relationship ◽

Anti Hiv ◽

Hiv 1

AbstractThe discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination, and instead that it would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain super-physiologic numbers of bNAb precursor expressing B cells and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti-HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center B cell recrutiment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the germinal center when there are as few as 10 such cells per mouse. However, at low precursor frequencies the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to germinal centers is variable and dependent on re-circulation.Significance statementAn essential requirement for an HIV-vaccine is to elicit antibodies to conserved regions of the spike protein (Env) becasue these antibodies can protect against infection. Although broadly neutralizing antibodies develop naturally in rare individuals after prolongued HIV infection, eliciting them by vaccination has only been possible in artificial knock-in mouse models wherein the number of B cells expressing the antibody precursor is super-physiologic. To understand the relationship between precursor frequency, antigen affinity and germinal center recruitment we have performed adoptive transfer experiments in which fixed numbers of precursor cells are engrafted in wild type mice. Our results provide a framework for understanding how precursor frequency and antigen affinity shape humoral immunity to HIV.

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Tracking SARS-CoV-2 T cells with epitope-T-cell receptor recognition models

10.1101/2020.09.09.289355 ◽

2020 ◽

Cited By ~ 1

Author(s):

Pieter Meysman ◽

Anna Postovskaya ◽

Nicolas De Neuter ◽

Benson Ogunjimi ◽

Kris Laukens

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Adaptive Immune Response ◽

Adaptive Immune System ◽

Cell Receptor ◽

Sequencing Data ◽

Adaptive Immune ◽

Cell Diversity ◽

Longitudinal Profiles

Much is still not understood about the human adaptive immune response to SARS-CoV-2, the causative agent of COVID-19. In this paper, we demonstrate the use of machine learning to classify SARS-CoV-2 epitope specific T-cell clonotypes in T-cell receptor (TCR) sequencing data. We apply these models to public TCR data and show how they can be used to study T-cell longitudinal profiles in COVID-19 patients to characterize how the adaptive immune system reacts to the SARS-CoV-2 virus. Our findings confirm prior knowledge that SARS-CoV-2 reactive T-cell diversity increases over the course of disease progression. However our results show a difference between those T cells that react to epitope unique to SARS-CoV-2, which show a more prominent increase, and those T cells that react to epitopes common to other coronaviruses, which begin at a higher baseline.

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DeepTCR is a deep learning framework for revealing sequence concepts within T-cell repertoires

Nature Communications ◽

10.1038/s41467-021-21879-w ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

John-William Sidhom ◽

H. Benjamin Larman ◽

Drew M. Pardoll ◽

Alexander S. Baras

Keyword(s):

Deep Learning ◽

T Cell ◽

Adaptive Immune System ◽

Cell Receptor ◽

Rna Seq ◽

Sequencing Data ◽

Learning Framework ◽

Adaptive Immune ◽

Gene Usage

AbstractDeep learning algorithms have been utilized to achieve enhanced performance in pattern-recognition tasks. The ability to learn complex patterns in data has tremendous implications in immunogenomics. T-cell receptor (TCR) sequencing assesses the diversity of the adaptive immune system and allows for modeling its sequence determinants of antigenicity. We present DeepTCR, a suite of unsupervised and supervised deep learning methods able to model highly complex TCR sequencing data by learning a joint representation of a TCR by its CDR3 sequences and V/D/J gene usage. We demonstrate the utility of deep learning to provide an improved ‘featurization’ of the TCR across multiple human and murine datasets, including improved classification of antigen-specific TCRs and extraction of antigen-specific TCRs from noisy single-cell RNA-Seq and T-cell culture-based assays. Our results highlight the flexibility and capacity for deep neural networks to extract meaningful information from complex immunogenomic data for both descriptive and predictive purposes.

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Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies

Journal of Experimental Medicine ◽

10.1084/jem.20122824 ◽

2013 ◽

Vol 210 (4) ◽

pp. 655-663 ◽

Cited By ~ 195

Author(s):

Andrew T. McGuire ◽

Sam Hoot ◽

Anita M. Dreyer ◽

Adriana Lippy ◽

Andrew Stuart ◽

...

Keyword(s):

Binding Site ◽

Neutralizing Antibodies ◽

Variable Region ◽

Neutralizing Antibody ◽

Glycosylation Site ◽

Affinity Maturation ◽

Broadly Neutralizing Antibodies ◽

Cd4 Binding Site ◽

Broadly Neutralizing Antibody ◽

Hiv Envelope

Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions.

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Structural basis for germline antibody recognition of HIV-1 immunogens

eLife ◽

10.7554/elife.13783 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 37

Author(s):

Louise Scharf ◽

Anthony P West ◽

Stuart A Sievers ◽

Courtney Chen ◽

Siduo Jiang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Affinity Maturation ◽

Structural Basis ◽

Binding Modes ◽

Broadly Neutralizing Antibodies ◽

Antibody Recognition ◽

Immunogen Design ◽

Cd4 Binding Site ◽

Modified Forms ◽

Hiv 1

Efforts to elicit broadly neutralizing antibodies (bNAbs) against HIV-1 require understanding germline bNAb recognition of HIV-1 envelope glycoprotein (Env). The VRC01-class bNAb family derived from the VH1-2*02 germline allele arose in multiple HIV-1–infected donors, yet targets the CD4-binding site on Env with common interactions. Modified forms of the 426c Env that activate germline-reverted B cell receptors are candidate immunogens for eliciting VRC01-class bNAbs. We present structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb–426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. Unlike typical antibody-antigen interactions, VRC01–class germline antibodies exhibited preformed antigen-binding conformations for recognizing immunogens. Affinity maturation introduced substitutions increasing induced-fit recognition and electropositivity, potentially to accommodate negatively-charged complex-type N-glycans on gp120. These results provide general principles relevant to the unusual evolution of VRC01–class bNAbs and guidelines for structure-based immunogen design.

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Targeting HIV using Structure-Based Rational Design of Antibodies

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314098805 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C119-C119

Author(s):

Ron Diskin ◽

Johannes Scheid ◽

Anthony West ◽

Florian Klein ◽

Michel Nussenzweig ◽

...

Keyword(s):

Binding Site ◽

Neutralizing Antibodies ◽

Rational Design ◽

Passive Immunization ◽

Broadly Neutralizing Antibodies ◽

X Ray Crystallography ◽

Cd4 Binding Site ◽

Topical Microbicides ◽

Anti Hiv ◽

New Strategies

Isolating and studying broadly anti HIV neutralizing antibodies from infected individuals is a major effort in the combat against HIV. We hope to gain better understanding for vaccine design by elucidating the exact epitope of such antibodies. Furthermore, by providing evermore potent and broadly neutralizing antibodies new strategies like passive immunization or using antibodies as topical microbicides for HIV prevention become feasible. One class of promising antibodies is anti CD4 binding site antibodies. Such antibodies can show exceptional potency and breadth. We used X-ray crystallography to study the structure of NIH45-46, one of the most potent anti CD4 binding site antibodies ever described in complex with gp120, the HIV receptor binding domain. Our structural analysis identified a region in the inner domain of gp120 that is important for the binding and neutralization of NIH45-46 (Diskin et al., 2011). This region is contacted by a four-residue insertion in CDRH3 that does not exist in VRC01, a less potent clonal member of NIH45-46. We further used structure-based rational design to improve NIH45-46. By replacing Gly54 in the CDRH2 with a tryptophan we allowed NIH45-46G54W to bind a unique hydrophobic pocket on the surface of gp120 that is normally accommodating Phe43 of CD4. Remarkably, NIH45-46G54W shows increase both in breadth and potency compared with NIH45-46 (Diskin et al., 2011). We took this approach further and engineered NIH45-46G54W to bind a conserved glycan on gp120. This effort resulted with the most potent and broadly neutralizing anti HIV antibody ever described (Diskin et al., 2013). I will present this work and additional efforts to modify NIH45-46 to accommodate potential escape mutations of HIV.

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Design of immunogens to elicit broadly neutralizing antibodies against HIV targeting the CD4 binding site

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2018338118 ◽

2021 ◽

Vol 118 (9) ◽

pp. e2018338118

Author(s):

Simone Conti ◽

Kevin J. Kaczorowski ◽

Ge Song ◽

Katelyn Porter ◽

Raiees Andrabi ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Affinity Maturation ◽

Effective Vaccine ◽

Broadly Neutralizing Antibodies ◽

Aids Epidemic ◽

Hiv Virus ◽

Hiv Antibodies ◽

Cd4 Binding Site ◽

Precursor B Cells ◽

Set Up

A vaccine which is effective against the HIV virus is considered to be the best solution to the ongoing global HIV/AIDS epidemic. In the past thirty years, numerous attempts to develop an effective vaccine have been made with little or no success, due, in large part, to the high mutability of the virus. More recent studies showed that a vaccine able to elicit broadly neutralizing antibodies (bnAbs), that is, antibodies that can neutralize a high fraction of global virus variants, has promise to protect against HIV. Such a vaccine has been proposed to involve at least three separate stages: First, activate the appropriate precursor B cells; second, shepherd affinity maturation along pathways toward bnAbs; and, third, polish the Ab response to bind with high affinity to diverse HIV envelopes (Env). This final stage may require immunization with a mixture of Envs. In this paper, we set up a framework based on theory and modeling to design optimal panels of antigens to use in such a mixture. The designed antigens are characterized experimentally and are shown to be stable and to be recognized by known HIV antibodies.

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HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽

10.3390/v13050852 ◽

2021 ◽

Vol 13 (5) ◽

pp. 852

Author(s):

Ashley Lauren Bennett ◽

Rory Henderson

Keyword(s):

Host Cell ◽

Conformational Changes ◽

Neutralizing Antibodies ◽

Critical Role ◽

Cell Receptor ◽

Broadly Neutralizing Antibodies ◽

Structural Mapping ◽

Host Cell Receptor ◽

Immunogen Design ◽

Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

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