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Article ; Online: A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice

Masayuki Kuraoka / Clare Burn Aschner / Ian W. Windsor / Aakash Mahant Mahant / Scott J. Garforth / Susan Luozheng Kong / Jacqueline M. Achkar / Steven C. Almo / Garnett Kelsoe / Betsy C. Herold

The Journal of Clinical Investigation, Vol 133, Iss

2023 Volume 3

Abstract: There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. ... ...

Abstract	There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2–vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo–electron microscopic structure of the Fab–glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.
Keywords	Infectious disease ; Vaccines ; Medicine ; R
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 multi-antigen protein microarray for detailed characterization of antibody responses in COVID-19 patients

Alev Celikgil / Aldo B. Massimi / Antonio Nakouzi / Natalia G. Herrera / Nicholas C. Morano / James H. Lee / Hyun ah Yoon / Scott J. Garforth / Steven C. Almo

PLoS ONE, Vol 18, Iss

2023 Volume 2

Abstract: Antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target multiple epitopes on different domains of the spike protein, and other SARS-CoV-2 proteins. We developed a SARS-CoV-2 multi-antigen protein microarray with the ... ...

Abstract	Antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target multiple epitopes on different domains of the spike protein, and other SARS-CoV-2 proteins. We developed a SARS-CoV-2 multi-antigen protein microarray with the nucleocapsid, spike and its domains (S1, S2), and variants with single (D614G, E484K, N501Y) or double substitutions (N501Y/Deletion69/70), allowing a more detailed high-throughput analysis of the antibody repertoire following infection. The assay was demonstrated to be reliable and comparable to ELISA. We analyzed antibodies from 18 COVID-19 patients and 12 recovered convalescent donors. The S IgG level was higher than N IgG in most of the COVID-19 patients, and the receptor-binding domain of S1 showed high reactivity, but no antibodies were detected against the heptad repeat domain 2 of S2. Furthermore, antibodies were detected against S variants with single and double substitutions in COVID-19 patients who were infected with SARS-CoV-2 early in the pandemic. Here we demonstrated that the SARS-CoV-2 multi-antigen protein microarray is a powerful tool for detailed characterization of antibody responses, with potential utility in understanding the disease progress and assessing current vaccines and therapies against evolving SARS-CoV-2.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 multi-antigen protein microarray for detailed characterization of antibody responses in COVID-19 patients.

Alev Celikgil / Aldo B Massimi / Antonio Nakouzi / Natalia G Herrera / Nicholas C Morano / James H Lee / Hyun Ah Yoon / Scott J Garforth / Steven C Almo

PLoS ONE, Vol 18, Iss 2, p e

2023 Volume 0276829

Abstract	Antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target multiple epitopes on different domains of the spike protein, and other SARS-CoV-2 proteins. We developed a SARS-CoV-2 multi-antigen protein microarray with the nucleocapsid, spike and its domains (S1, S2), and variants with single (D614G, E484K, N501Y) or double substitutions (N501Y/Deletion69/70), allowing a more detailed high-throughput analysis of the antibody repertoire following infection. The assay was demonstrated to be reliable and comparable to ELISA. We analyzed antibodies from 18 COVID-19 patients and 12 recovered convalescent donors. The S IgG level was higher than N IgG in most of the COVID-19 patients, and the receptor-binding domain of S1 showed high reactivity, but no antibodies were detected against the heptad repeat domain 2 of S2. Furthermore, antibodies were detected against S variants with single and double substitutions in COVID-19 patients who were infected with SARS-CoV-2 early in the pandemic. Here we demonstrated that the SARS-CoV-2 multi-antigen protein microarray is a powerful tool for detailed characterization of antibody responses, with potential utility in understanding the disease progress and assessing current vaccines and therapies against evolving SARS-CoV-2.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Lysine 65 Residue in HIV-1 Reverse Transcriptase Function and in Nucleoside Analog Drug Resistance

Scott J. Garforth / Chisanga Lwatula / Vinayaka R. Prasad

Viruses, Vol 6, Iss 10, Pp 4080-

2014 Volume 4094

Abstract: Mutations in HIV-1 reverse transcriptase (RT) that confer nucleoside analog RT inhibitor resistance have highlighted the functional importance of several active site residues (M184, Q151 and K65) in RT catalytic function. Of these, K65 residue is notable ...

Abstract	Mutations in HIV-1 reverse transcriptase (RT) that confer nucleoside analog RT inhibitor resistance have highlighted the functional importance of several active site residues (M184, Q151 and K65) in RT catalytic function. Of these, K65 residue is notable due to its pivotal position in the dNTP-binding pocket, its involvement in nucleoside analog resistance and polymerase fidelity. This review focuses on K65 residue and summarizes a substantial body of biochemical and structural studies of its role in RT function and the functional consequences of the K65R mutation.
Keywords	HIV-1 reverse transcriptase ; NRTI analog resistance ; K65R mutation ; HIV-1 drug resistance ; reverse transcriptase function ; polymerase fidelity ; Microbiology ; QR1-502 ; Science ; Q
Language	English
Publishing date	2014-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human immunomodulatory ligand B7-1 mediates synaptic remodeling via the p75 neurotrophin receptor

Nicholas C. Morano / Roshelle S. Smith / Victor Danelon / Ryan Schreiner / Uttsav Patel / Natalia G. Herrera / Carla Smith / Steven M. Olson / Michelle K. Laerke / Alev Celikgil / Scott J. Garforth / Sarah C. Garrett-Thomson / Francis S. Lee / Barbara L. Hempstead / Steven C. Almo

The Journal of Clinical Investigation, Vol 132, Iss

2022 Volume 22

Abstract: Cell surface receptors, ligands, and adhesion molecules underlie development, circuit formation, and synaptic function of the central nervous system and represent important therapeutic targets for many neuropathologies. The functional contributions of ... ...

Abstract	Cell surface receptors, ligands, and adhesion molecules underlie development, circuit formation, and synaptic function of the central nervous system and represent important therapeutic targets for many neuropathologies. The functional contributions of interactions between cell surface proteins of neurons and nonneuronal cells have not been fully addressed. Using an unbiased protein-protein interaction screen, we showed that the human immunomodulatory ligand B7-1 (hB7-1) interacts with the p75 neurotrophin receptor (p75NTR) and that the B7-1:p75NTR interaction is a recent evolutionary adaptation present in humans and other primates, but absent in mice, rats, and other lower mammals. The surface of hB7-1 that engages p75NTR overlaps with the hB7-1 surface involved in CTLA-4/CD28 recognition, and these molecules directly compete for binding to p75NTR. Soluble or membrane-bound hB7-1 altered dendritic morphology of cultured hippocampal neurons, with loss of the postsynaptic protein PSD95 in a p75NTR-dependent manner. Abatacept, an FDA-approved therapeutic (CTLA-4–hFc fusion) inhibited these processes. In vivo injection of hB7-1 into the murine subiculum, a hippocampal region affected in Alzheimer’s disease, resulted in p75NTR-dependent pruning of dendritic spines. Here, we report the biochemical interaction between B7-1 and p75NTR, describe biological effects on neuronal morphology, and identify a therapeutic opportunity for treatment of neuroinflammatory diseases.
Keywords	Neuroscience ; Medicine ; R
Subject code	571
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mechanistic dissection of the PD-L1:B7-1 co-inhibitory immune complex.

Sarah C Garrett-Thomson / Aldo Massimi / Elena V Fedorov / Jeffrey B Bonanno / Lisa Scandiuzzi / Brandan Hillerich / Ronald D Seidel / James D Love / Scott J Garforth / Chandan Guha / Steven C Almo

PLoS ONE, Vol 15, Iss 6, p e

2020 Volume 0233578

Abstract: The B7 family represents one of the best-studied subgroups within the Ig superfamily, yet new interactions continue to be discovered. However, this binding promiscuity represents a major challenge for defining the biological contribution of each specific ...

Abstract	The B7 family represents one of the best-studied subgroups within the Ig superfamily, yet new interactions continue to be discovered. However, this binding promiscuity represents a major challenge for defining the biological contribution of each specific interaction. We developed a strategy for addressing these challenges by combining cell microarray and high-throughput FACS methods to screen for promiscuous binding events, map binding interfaces, and generate functionally selective reagents. Applying this approach to the interactions of mPD-L1 with its receptor mPD-1 and its ligand mB7-1, we identified the binding interface of mB7-1 on mPD-L1 and as a result generated mPD-L1 mutants with binding selectivity for mB7-1 or mPD-1. Next, using a panel of mB7-1 mutants, we mapped the binding sites of mCTLA-4, mCD28 and mPD-L1. Surprisingly, the mPD-L1 binding site mapped to the dimer interface surface of mB7-1, placing it distal from the CTLA-4/CD28 recognition surface. Using two independent approaches, we demonstrated that mPD-L1 and mB7-1 bind in cis, consistent with recent reports from Chaudhri A et al. and Sugiura D et al. We further provide evidence that while CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, they can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. These observations offer new functional insights into the regulatory mechanisms associated with this group of B7 family proteins and provide new tools to elucidate their function in vitro and in vivo.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Longitudinally monitored immune biomarkers predict the timing of COVID-19 outcomes.

Gorka Lasso / Saad Khan / Stephanie A Allen / Margarette Mariano / Catalina Florez / Erika P Orner / Jose A Quiroz / Gregory Quevedo / Aldo Massimi / Aditi Hegde / Ariel S Wirchnianski / Robert H Bortz / Ryan J Malonis / George I Georgiev / Karen Tong / Natalia G Herrera / Nicholas C Morano / Scott J Garforth / Avinash Malaviya /

Ahmed Khokhar / Ethan Laudermilch / M Eugenia Dieterle / J Maximilian Fels / Denise Haslwanter / Rohit K Jangra / Jason Barnhill / Steven C Almo / Kartik Chandran / Jonathan R Lai / Libusha Kelly / Johanna P Daily / Olivia Vergnolle

PLoS Computational Biology, Vol 18, Iss 1, p e

2022 Volume 1009778

Abstract: The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models ...

Abstract	The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models rely on static demographic features and clinical values obtained upon hospitalization. However, time-dependent biomarkers associated with COVID-19 severity, such as antibody titers, can substantially contribute to the development of more accurate outcome models. Here we show that models trained on immune biomarkers, longitudinally monitored throughout hospitalization, predicted mortality and were more accurate than models based on demographic and clinical data upon hospital admission. Our best-performing predictive models were based on the temporal analysis of anti-SARS-CoV-2 Spike IgG titers, white blood cell (WBC), neutrophil and lymphocyte counts. These biomarkers, together with C-reactive protein and blood urea nitrogen levels, were found to correlate with severity of disease and mortality in a time-dependent manner. Shapley additive explanations of our model revealed the higher predictive value of day post-symptom onset (PSO) as hospitalization progresses and showed how immune biomarkers contribute to predict mortality. In sum, we demonstrate that the kinetics of immune biomarkers can inform clinical models to serve as a powerful monitoring tool for predicting fatality risk in hospitalized COVID-19 patients, underscoring the importance of contextualizing clinical parameters according to their time post-symptom onset.
Keywords	Biology (General) ; QH301-705.5
Subject code	310
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Utilization of a deoxynucleoside diphosphate substrate by HIV reverse transcriptase.

Scott J Garforth / Michael A Parniak / Vinayaka R Prasad

PLoS ONE, Vol 3, Iss 4, p e

2008 Volume 2074

Abstract: Deoxynucleoside triphosphates (dNTPs) are the normal substrates for DNA synthesis catalyzed by polymerases such as HIV-1 reverse transcriptase (RT). However, substantial amounts of deoxynucleoside diphosphates (dNDPs) are also present in the cell. Use of ...

Abstract	Deoxynucleoside triphosphates (dNTPs) are the normal substrates for DNA synthesis catalyzed by polymerases such as HIV-1 reverse transcriptase (RT). However, substantial amounts of deoxynucleoside diphosphates (dNDPs) are also present in the cell. Use of dNDPs in HIV-1 DNA synthesis could have significant implications for the efficacy of nucleoside RT inhibitors such as AZT which are first line therapeutics for treatment of HIV infection. Our earlier work on HIV-1 reverse transcriptase (RT) suggested that the interaction between the gamma-phosphate of the incoming dNTP and RT residue K65 in the active site is not essential for dNTP insertion, implying that this polymerase may be able to insert dNDPs in addition to dNTPs.We examined the ability of recombinant wild type (wt) and mutant RTs with substitutions at residue K65 to utilize a dNDP substrate in primer extension reactions. We found that wild type HIV-1 RT indeed catalyzes incorporation of dNDP substrates whereas RT with mutations of residue K65 were unable to catalyze this reaction. Wild type HIV-1 RT also catalyzed the reverse reaction, inorganic phosphate-dependent phosphorolysis. Nucleotide-mediated phosphorolytic removal of chain-terminating 3'-terminal nucleoside inhibitors such as AZT forms the basis for HIV-1 resistance to such drugs, and this removal is enhanced by thymidine analog mutations (TAMs). We found that both wt and TAM-containing RTs were able to catalyze Pi-mediated phosphorolysis of 3'-terminal AZT at physiological levels of Pi with an efficacy similar to that for ATP-dependent AZT-excision.We have identified two new catalytic functions of HIV-1 RT, the use of dNDPs as substrates for DNA synthesis, and the use of Pi as substrate for phosphorolytic removal of primer 3'-terminal nucleotides. The ability to insert dNDPs has been documented for only one other DNA polymerase, the RB69 DNA polymerase and the reverse reaction employing inorganic phosphate has not been documented for any DNA polymerase. Importantly, our results show that ...
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2008-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acid cycle of Mycobacterium tuberculosis.

Anthony D Baughn / Scott J Garforth / Catherine Vilchèze / William R Jacobs

PLoS Pathogens, Vol 5, Iss 11, p e

2009 Volume 1000662

Abstract: Aerobic organisms have a tricarboxylic acid (TCA) cycle that is functionally distinct from those found in anaerobic organisms. Previous reports indicate that the aerobic pathogen Mycobacterium tuberculosis lacks detectable alpha-ketoglutarate (KG) ... ...

Abstract	Aerobic organisms have a tricarboxylic acid (TCA) cycle that is functionally distinct from those found in anaerobic organisms. Previous reports indicate that the aerobic pathogen Mycobacterium tuberculosis lacks detectable alpha-ketoglutarate (KG) dehydrogenase activity and drives a variant TCA cycle in which succinyl-CoA is replaced by succinic semialdehyde. Here, we show that M. tuberculosis expresses a CoA-dependent KG dehydrogenase activity, albeit one that is typically found in anaerobic bacteria. Unlike most enzymes of this family, the M. tuberculosis KG: ferredoxin oxidoreductase (KOR) is extremely stable under aerobic conditions. This activity is absent in a mutant strain deleted for genes encoding a previously uncharacterized oxidoreductase, and this strain is impaired for aerobic growth in the absence of sufficient amounts of CO(2). Interestingly, inhibition of the glyoxylate shunt or exclusion of exogenous fatty acids alleviates this growth defect, indicating the presence of an alternate pathway that operates in the absence of beta-oxidation. Simultaneous disruption of KOR and the first enzyme of the succinic semialdehyde pathway (KG decarboxylase; KGD) results in strict dependence upon the glyoxylate shunt for growth, demonstrating that KG decarboxylase is also functional in M. tuberculosis intermediary metabolism. These observations demonstrate that unlike most organisms M. tuberculosis utilizes two distinct TCA pathways from KG, one that functions concurrently with beta-oxidation (KOR-dependent), and one that functions in the absence of beta-oxidation (KGD-dependent). As these pathways are regulated by metabolic cues, we predict that their differential utilization provides an advantage for growth in different environments within the host.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2009-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Characterization of the SARS-CoV‑2 S Protein

Natalia G. Herrera / Nicholas C. Morano / Alev Celikgil / George I. Georgiev / Ryan J. Malonis / James H. Lee / Karen Tong / Olivia Vergnolle / Aldo B. Massimi / Laura Y. Yen / Alex J. Noble / Mykhailo Kopylov / Jeffrey B. Bonanno / Sarah C. Garrett-Thomson / David B. Hayes / Robert H. Bortz / Ariel S. Wirchnianski / Catalina Florez / Ethan Laudermilch /

Denise Haslwanter / J. Maximilian Fels / M. Eugenia Dieterle / Rohit K. Jangra / Jason Barnhill / Amanda Mengotto / Duncan Kimmel / Johanna P. Daily / Liise-anne Pirofski / Kartik Chandran / Michael Brenowitz / Scott J. Garforth / Edward T. Eng / Jonathan R. Lai / Steven C. Almo

ACS Omega, Vol 6, Iss 1, Pp 85-

Biophysical, Biochemical, Structural, and Antigenic Analysis

2020 Volume 102

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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