Publications by authors named "Yaming Shan"

49 Publications

A novel hydrophilic fluorescent probe for Cu detection and imaging in HeLa cells.

RSC Adv 2021 Mar 10;11(17):10264-10271. Epub 2021 Mar 10.

College of Chemistry, Jilin University Changchun 130021 China

Copper is an essential element in living systems and plays an important role in human physiology; therefore, methods to detect the concentration of copper ions in living organisms are important. Herein, we report a highly water-soluble naphthalimide-based fluorescent probe that can be used for the detection of Cu. The probe, BNQ, has high selectivity and sensitivity. The fluorescence intensity of the probe at 520 nm was visible to the naked eye under a UV lamp; upon the gradual addition of Cu, there was a colour change from green to nearly colourless. Furthermore, the detection limit of BNQ for Cu was 45.5 nM. The detection mechanism was investigated using a Job's plot and density functional theory (DFT) calculations. In addition, owing to great biocompatibility, we were able to successfully use BNQ to detect Cu in living HeLa cells with low toxicity.
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http://dx.doi.org/10.1039/d0ra09894aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8695708PMC
March 2021

An insulin growth factor-I/II-neutralizing monoclonal antibody in combination with epidermal growth factor receptor inhibitors potently inhibits tumor cell growth.

J Cancer 2022 21;13(6):1830-1836. Epub 2022 Mar 21.

Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.

The insulin-like growth factors (IGFs), IGF-1 and IGF-II, which bind to the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR), have been implicated in the growth, survival, and metastasis of tumor cells. We have previously identified a novel human monoclonal antibody (mAb), m708.5, which neutralizes both human IGF-I and IGF-II, and potently inhibits phosphorylation of the IGF-1R and the IR in breast cancer cells. In this study, m708.5 exhibited very strong synergy with the epidermal growth factor receptor (EGFR) inhibitor gefitinib, and synergy with chemotherapeutic agents against either neuroblastoma or breast cancer cells. In xenografted models, the combination of m708.5 and gefitinib significantly inhibited LAN-1 cell growth better than single agent alone. Taken together, these results support the clinical development of m708.5 for solid tumors with potential for synergy with chemotherapy and EGFR inhibitors.
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http://dx.doi.org/10.7150/jca.69064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990425PMC
March 2022

A self-assembling nanoparticle vaccine targeting the conserved epitope of influenza virus hemagglutinin stem elicits a cross-protective immune response.

Nanoscale 2022 Feb 24;14(8):3250-3260. Epub 2022 Feb 24.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.

Various vaccine strategies have been developed to provide broad protection against diverse influenza viruses. The hemagglutinin (HA) stem is the major potential target of these vaccines. Enhancing immunogenicity and eliciting cross-protective immune responses are critical for HA stem-based vaccine designs. In this study, the A helix (Ah) and CD helix (CDh) from the HA stem were fused with ferritin, individually, or in tandem, yielding Ah-f, CDh-f and (A + CD)h-f nanoparticles (NPs), respectively. These NPs were produced through a prokaryotic expression system. After three immunizations with AS03-adjuvanted NPs in BALB/c mice the subcutaneous route, CDh-f and (A + CD)h-f induced robust humoral and cellular immune responses. Furthermore, CDh-f and (A + CD)h-f conferred complete protection against a lethal challenge of H3N2 virus, while no remarkable immune responses and protective effects were detected in the Ah-f group. These results indicate that the CDh-based nanovaccine represents a promising vaccine platform against influenza, and the epitope-conjugated ferritin NPs may be a potential vaccine platform against other infectious viruses, such as SARS-COV-2.
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http://dx.doi.org/10.1039/d1nr08460gDOI Listing
February 2022

Hemagglutinin-based DNA vaccines containing trimeric self-assembling nanoparticles confer protection against influenza.

J Leukoc Biol 2022 Jan 17. Epub 2022 Jan 17.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.

Influenza viruses continue to threaten public health, and currently available vaccines provide insufficient immunity against seasonal and pandemic influenza. The use of recombinant trimeric hemagglutinin (HA) as an Ag provides an attractive alternative to current influenza vaccines. Aiming to develop an effective vaccine with rapid production, robust immunogenicity, and high protective efficiency, a DNA vaccine was designed by fusing influenza virus HA with self-assembled ferritin nanoparticles, denoted as HA-F. This candidate vaccine was prepared and purified in a 293-6E cell eukaryotic expression system. After BALB/c mice were immunized with 100 μg of HA-F DNA 3 times, HA-F elicited significant HA-specific humoral immunity and T cell immune responses. The HA-F DNA vaccine also conferred protection in mice against a lethal infection of homologous A/17/California/2009/38 (H1N1) virus. These results suggest that the HA-F DNA vaccine is a competitive vaccine candidate and presents a promising vaccination approach against influenza viruses.
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http://dx.doi.org/10.1002/JLB.6A1021-535RDOI Listing
January 2022

Self-assembling ferritin nanoparticles coupled with linear sequences from canine distemper virus haemagglutinin protein elicit robust immune responses.

J Nanobiotechnology 2022 Jan 10;20(1):32. Epub 2022 Jan 10.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, Jilin, China.

Background: Canine distemper virus (CDV), which is highly infectious, has caused outbreaks of varying scales in domestic and wild animals worldwide, so the development of a high-efficiency vaccine has broad application prospects. Currently, the commercial vaccine of CDV is an attenuated vaccine, which has the disadvantages of a complex preparation process, high cost and safety risk. It is necessary to develop a safe and effective CDV vaccine that is easy to produce on a large scale. In this study, sequences of CDV haemagglutinin (HA) from the Yanaka strain were aligned, and three potential linear sequences, termed YaH, YaH, and YaH, were collected. To increase the immunogenicity of the epitopes, ferritin was employed as a self-assembling nanoparticle element. The ferritin-coupled forms were termed YaHF, YaHF, and YaHF, respectively. A full-length HA sequence coupled with ferritin was also constructed as a DNA vaccine to compare the immunogenicity of nanoparticles in prokaryotic expression.

Result: The self-assembly morphology of the proteins from prokaryotic expression was verified by transmission electron microscopy. All the proteins self-assembled into nanoparticles. The expression of the DNA vaccine YaHF in HEK-293T cells was also confirmed in vitro. After subcutaneous injection of epitope nanoparticles or intramuscular injection of DNA YaHF, all vaccines induced strong serum titres, and long-term potency of antibodies in serum could be detected after 84 days. Strong anti-CDV neutralizing activities were observed in both the YaHF group and YaHF group. According to antibody typing and cytokine detection, YaHF can induce both Th1 and Th2 immune responses. The results of flow cytometry detection indicated that compared with the control group, all the immunogens elicited an increase in CD3. Simultaneously, the serum antibodies induced by YaHF and YaHF could significantly enhance the ADCC effect compared with the control group, indicating that the antibodies in the serum effectively recognized the antigens on the cell surface and induced NK cells to kill infected cells directly.

Conclusions: YaHF self-assembling nanoparticle obtained by prokaryotic expression has no less of an immune effect than YaHF, and H has great potential to become a key target for the easy and rapid preparation of epitope vaccines.
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http://dx.doi.org/10.1186/s12951-021-01229-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8744384PMC
January 2022

Surface-Functionalized Silica-Coated Calcium Phosphate Nanoparticles Efficiently Deliver DNA-Based HIV-1 Trimeric Envelope Vaccines against HIV-1.

ACS Appl Mater Interfaces 2021 Nov 4;13(45):53630-53645. Epub 2021 Nov 4.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.

Human immunodeficiency virus type 1 (HIV-1) infection remains one of the worst crises in global health. The prevention of HIV-1 infection is a crucial task that needs to be addressed due to the absence of a licensed vaccine against HIV-1. DNA vaccines present a promising alternative approach to combat HIV-1 infection due to their excellent safety profile, lack of severe side effects, and relatively rapid fabrication. Traditional vaccines composed of a monomeric envelope or peptide fragments have been indicated to lack protective efficacy mediated by inducing HIV-1-specific neutralizing antibodies in clinical trials. The immunogenicity and protection against HIV-1 induced by DNA vaccines are limited due to the poor uptake of these vaccines by antigen-presenting cells and their ready degradation by DNases and lysosomes. To address these issues of naked DNA vaccines, we described the feasibility of CpG-functionalized silica-coated calcium phosphate nanoparticles (SCPs) for efficiently delivering DNA-based HIV-1 trimeric envelope vaccines against HIV-1. Vaccines comprising the soluble BG505 SOSIP.664 trimer fused to the GCN4-based isoleucine zipper or bacteriophage T4 fibritin foldon motif with excellent simulation of the native HIV-1 envelope were chosen as trimer-based vaccine platforms. Our results showed that SCP-based DNA immunization could significantly induce both broad humoral immune responses and potent cellular immune responses compared to naked DNA vaccination in vivo. To the best of our knowledge, this study is the first to assess the feasibility of CpG-functionalized SCPs for efficiently delivering DNA vaccines expressing a native-like HIV-1 trimer. These CpG-functionalized SCPs for delivering DNA-based HIV-1 trimeric envelope vaccines may lead to the development of promising vaccine candidates against HIV-1.
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http://dx.doi.org/10.1021/acsami.1c16989DOI Listing
November 2021

A novel mitochondrial-targeting fluorescent probe based on 1,4-dihydropyridine to visualize and monitor the viscosity of live cells and mice .

Anal Methods 2021 09 30;13(37):4238-4245. Epub 2021 Sep 30.

College of Chemistry, Jilin University, Changchun 130021, Jilin, China.

Cell viscosity is related to some diseases, such as diabetes, atherosclerosis, and Alzheimer's disease. These diseases can cause abnormal viscosity of the cell mitochondrial matrix. 1,4-Dihydropyridine (DHP) is an important organic compound with biological activity and is widely used in drug research. However, there are few studies on its optical properties, especially in the design of viscous fluorescent probes. In this study, a fluorescent probe for viscosity detection using 1,4-dihydropyridine as the fluorophore and indole iodide salt as the recognition group was designed and synthesized. The probe has the advantages of a deep-red emission, low cytotoxicity, good biocompatibility and excellent anti-interference ability. In addition, the probe also has the ability to target mitochondria and has been successfully applied to the detection of the viscosity response of HeLa cells and living mice, and has good clinical application potential.
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http://dx.doi.org/10.1039/d1ay01206aDOI Listing
September 2021

A literature review of MRI techniques used to detect amyloid-beta plaques in Alzheimer's disease patients.

Ann Palliat Med 2021 Sep 17;10(9):10062-10074. Epub 2021 Sep 17.

Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, China.

Objective: In this review, we aim to provide an overview of the imaging techniques most commonly used to study Alzheimer's disease (AD).

Background: Neuroimaging biomarkers can be used to evaluate these abnormalities, improve the ability of early diagnosis and help predict disease progression. These signs mainly include local brain atrophy on structural MRI, hypometabolic foci, and amyloid plaque deposition in the brain detected by specific imaging. These techniques not only have their unique advantages, but can complement each other in multimodal imaging evaluation of patients with cognitive impairment and dementia.

Methods: A literature search was performed on PubMed using the search term combinations "Alzheimer's disease", "Amyloid-beta plaques", and "MRI". We discuss various magnetic resonance imaging (MRI) based techniques, including direct imaging, indirect imaging, amyloid-beta (Aβ) plaque and radiomics, Hybrid PET/MRI and MRI imaging technology in the future, placing a special emphasis on multimodal imaging, and focus our review on the MRI features of Aβ plaques (AD biomarkers).

Conclusions: After a lot of research and reasonable selection, multimodal imaging composed of MRI and PET can significantly improve the diagnosis and treatment of AD patients, and the complementary information can be obtained by the new PET/MR instrument at the same time. The findings of this review emphasize that multimodal imaging is likely to be the preferred method for future AD research and clinical practice.
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http://dx.doi.org/10.21037/apm-21-825DOI Listing
September 2021

Broad and potent bispecific neutralizing antibody gene delivery using adeno-associated viral vectors for passive immunization against HIV-1.

J Control Release 2021 10 10;338:633-643. Epub 2021 Sep 10.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin 130012, China; Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin 130012, China. Electronic address:

Broadly neutralizing antibodies (bNAbs) possess favorable safety, and passive immunization using these can prevent or control human immunodeficiency virus type 1 (HIV-1) infection. However, bNAbs generally used for monotherapy (IC > 5 μg/mL) have limited breadth and potency and neutralize only 70-90% of all HIV-1 strains. To address the need for broader coverage of the HIV-1 epidemic and enhance the ability of bNAbs to target HIV-1, we fused the single-chain variable antibody fragment (scFv) of bNAbs (PG9, PGT123, or NIH45-46) with full-length ibalizumab (iMab) in an scFv-monoclonal antibody tandem format to construct bispecific bNAbs (BibNAbs). Additionally, we described the feasibility of BibNAb gene delivery mediated by recombinant adeno-associated virus 8 (rAAV8) for generating long-term expression with a single injection as opposed to short-term passive immunization requiring continuous injections. Our results showed that the expressed BibNAbs targeting two distinct epitopes exhibited neutralizing activity against 20 HIV-1 pseudoviruses in vitro. After injecting a single rAAV8 vector, the expression and neutralizing activity of the BibNAbs in serum were sustained for 24 weeks. To the best of our knowledge, very few studies have been published on BibNAb gene delivery using rAAV8 vectors against HIV-1. BibNAb gene delivery using rAAV8 vectors may be promising for passive immunization against HIV-1 infection.
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http://dx.doi.org/10.1016/j.jconrel.2021.09.006DOI Listing
October 2021

MicroRNAs Involved in the Therapeutic Functions of Noni ( L.) Fruit Juice in the Treatment of Acute Gouty Arthritis in Mice Induced with Monosodium Urate.

Foods 2021 Jul 15;10(7). Epub 2021 Jul 15.

College of Food Engineering, Jilin Engineering Normal University, Changchun 130052, China.

We investigated the functions of microRNAs in the therapeutic effects of noni ( L.) fruit juice on mouse models of acute gouty arthritis induced with monosodium urate (MSU). Compared with the model group (treated with MSU), mice in both the positive control group (treated with both MSU and colchicine) and noni fruit juice group (treated with MSU and noni fruit juice) showed a significantly decreased degree of paw swelling in 5 days, as well as the contents of two types of proinflammatory cytokines (i.e., NALP3 and TNF-α). Based on the next-generation sequencing technology, a total of 3896 microRNAs (234 known and 3662 novel) were identified in mice treated with noni fruit juice. A large amount of differentially expressed miRNAs were identified in the noni fruit juice group, suggesting the significant effects of noni fruit juice on the mice with acute gouty arthritis, while the different patterns of change in the numbers of both upregulated and downregulated miRNAs in both noni fruit juice and positive control groups indicated that the mice of acute gouty arthritis may be regulated by differential mechanisms between the treatments of noni fruit juice and colchicine. The target genes of microRNAs involved in the pathogenesis and pathology of acute gouty arthritis in mice were identified and further annotated by both Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Our results revealed the therapeutic effects of noni fruit juice on acute gouty arthritis in mice with a group of microRNAs involved in the pharmacological mechanisms of noni fruit juice, providing scientific evidence to support both the agricultural cultivation and pharmacological significance of noni plants.
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http://dx.doi.org/10.3390/foods10071638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308103PMC
July 2021

Expression and evaluation of porcine circovirus type 2 capsid protein mediated by recombinant adeno-associated virus 8.

J Vet Sci 2021 Jan;22(1):e8

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.

Background: Porcine circovirus type 2 (PCV2) is an important infectious pathogen implicated in porcine circovirus-associated diseases (PCVAD), which has caused significant economic losses in the pig industry worldwide.

Objectives: A suitable viral vector-mediated gene transfer platform for the expression of the capsid protein (Cap) is an attractive strategy.

Methods: In the present study, a recombinant adeno-associated virus 8 (rAAV8) vector was constructed to encode Cap (Cap-rAAV) and after gene transfer.

Results: The obtained results showed that Cap could be expressed in HEK293T cells and BABL/c mice. The results of lymphocytes proliferative, as well as immunoglobulin G (IgG) 2a and interferon-γ showed strong cellular immune responses induced by Cap-rAAV. The enzyme-linked immunosorbent assay titers obtained and the IgG1 and interleukin-4 levels showed that humoral immune responses were also induced by Cap-rAAV. Altogether, these results demonstrated that the rAAV8 vaccine Cap-rAAV can induce strong cellular and humoral immune responses, indicating a potential rAAV8 vaccine against PCV2.

Conclusions: The injection of rAAV8 encoding PCV2 Cap genes into muscle tissue can ensure long-term, continuous, and systemic expression.
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http://dx.doi.org/10.4142/jvs.2021.22.e8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850785PMC
January 2021

Identification of Linear Peptide Immunogens with Verified Broad-spectrum Immunogenicity from the Conserved Regions within the Hemagglutinin Stem Domain of H1N1 Influenza Virus.

Immunol Invest 2022 Feb 20;51(2):411-424. Epub 2020 Oct 20.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.

Background: Influenza A viruses (IAVs) induce acute respiratory disease and cause severe epidemics and pandemics. Since IAVs exhibit antigenic variation and genome reassortment, the development of broad-spectrum influenza vaccines is crucial. The stem of the hemagglutinin (HA) is highly conserved across IAV strains and thus has been explored in broad-spectrum influenza vaccine studies. The present study aimed to identify viral epitopes capable of eliciting effective host immune responses, which can be explored for the development of broad-spectrum non-strain specific prophylactic options against IAV.

Methods: In this study, a series of conserved linear sequences from the HA stem of IAV (H1N1) was recognized by sequence alignment and B/T-cell epitope prediction after being chemically coupled to the Keyhole Limpet Hemocyanin (KLH) protein. The predicted linear epitopes were identified by enzyme-linked immunosorbent assay (ELISA) after animal immunization and then fused with ferritin carriers.

Results: Three predicted linear epitopes with relatively strong immunogenicity, P3, P6 and P8 were fused with ferritin carriers P3F, P6F and P8F, respectively to further improve their immunogenicity. Antibody titre of the sera of mice immunized with the recombinant immunogens revealed the elicitation of specific antibody-binding activities by the identified sequences. While hemagglutinin-inhibition activities were not detected in the antisera, neutralizing antibodies against the H1 and H3 virus subtypes were detected by the microneutralization assay.

Conclusion: The linear epitopes fused with ferritin identified in this study can lay the foundation for future advancements in development of broad-spectrum subunit vaccine against IAV (H1N1), and give rise to the potential future applicability of ferritin-based antigen delivery nanoplatforms.
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http://dx.doi.org/10.1080/08820139.2020.1834579DOI Listing
February 2022

Exploration of Binding Mechanism of a Potential Neuraminidase Inhibitor from Herbaceous Plants by Molecular Simulation.

Int J Mol Sci 2020 Feb 3;21(3). Epub 2020 Feb 3.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, Jilin, China.

can cause diseases such as pneumonia. Broad-spectrum antibiotic therapy for is increasingly limited due to the emergence of drug-resistant strains. The development of novel drugs is still currently of focus. Abundant polyphenols have been demonstrated to have antivirus and antibacterial ability. Chlorogenic acid is one of the representatives that has been proven to have the potential to inhibit both the influenza virus and . However, for such a potential neuraminidase inhibitor, the interaction mechanism studies between chlorogenic acid and neuraminidase are rare. In the current study, the binding mechanism of chlorogenic acid and neuraminidase were investigated by molecular simulation. The results indicated that chlorogenic acid might establish the interaction with neuraminidase via hydrogen bonds, salt bridge, and cation-π. The vital residues involved Arg347, Ile348, Lys440, Asp372, Asp417, and Glu768. The side chain of Arg347 might form a cap-like structure to lock the chlorogenic acid to the active site. The results from binding energy calculation indicated that chlorogenic acid had strong binding potential with neuraminidase. The results predicted a detailed binding mechanism of a potential neuraminidase inhibitor, which will be provide a theoretical basis for the mechanism of new inhibitors.
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http://dx.doi.org/10.3390/ijms21031003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038148PMC
February 2020

Water-soluble fluorescent probe for simultaneous detection of cyanide, hypochlorite and bisulfite at different emission wavelengths.

Anal Biochem 2020 02 16;591:113539. Epub 2019 Dec 16.

Institute of Theoretical Chemistry, Laboratory of Theoretical and Computational Chemistry, Jilin University, Changchun, 130023, PR China. Electronic address:

A fluorescent probe that responds at distinct wavelengths upon exposure to cyanide, hypochlorite, and bisulfite was synthesized. As a result, an easy to apply analytical methodology was developed for the detection of these ions. The feasibility of this method was evaluated by theoretical calculations. The probe exhibited excellent solubility in the test solution (HO: DMF = 99: 1, v: v) with low detection limits for cyanide, hypochlorite and bisulfite (4.5 × 10  M, 4.9 × 10  M and 4.3 × 10  M respectively) showing distinct emission wavelengths for each ion without interference in practical application. Furthermore, the probe had low toxicity and was applied for the imaging experiments of cyanide, hypochlorite and bisulfite in living HeLa and MDCK cells.
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http://dx.doi.org/10.1016/j.ab.2019.113539DOI Listing
February 2020

Using near-infrared enhanced thermozyme and dual-conjugated Au nanorods for detection and targeted photothermal treatment of Alzheimer's disease.

Theranostics 2019 12;9(8):2268-2281. Epub 2019 Apr 12.

National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, Changchun, 130012, China.

Investigation of targeting inhibitors of Aβ aggregation, heme-Aβ peroxidase-like activity and efficient detectors of Aβ aggregation, are of therapeutic value and diagnostics significance for the treatment of Alzheimer's disease (AD). Due to the complex pathogenesis of AD, theranostics treatment with multiple functions are necessary. Herein we constructed the NIR absorption property of gold nanorods (GNRs) loaded with single chain variable fragment () 12B4 and thermophilic acylpeptide hydrolase (APH) ST0779 as a smart theranostic complex (GNRs-APH-, GAS), which possesses both rapid detection of Aβ aggregates and NIR photothermal treatment that effectively disassembles Aβ aggregates and inhibits Aβ-mediated toxicity. : We screened targeting anti-Aβ 12B4 and thermophilic acylpeptide hydrolase as amyloid-degrading enzyme, synthesized GAS gold nanorods complex. The GAS was evalued by Aβ inhibition and disaggregation assays, Aβ detection assays, Aβ mediated toxicity assays . delaying Aβ-induced paralysis in AD model of was also tested by GAS. : , GAS has a synergistic effect to inhibit and disassociate Aβ aggregates, in addition to decrease heme-Aβ peroxidase-like activity. In cultured cells, treatment with GAS reduces Aβ-induced cytotoxicity, while also delaying Aβ-mediated paralysis in CL4176 model of AD. Furthermore, the photothermal effect of the GAS upon NIR laser irradiation not only helps disassociate the Aβ aggregates but also boosts APH activity to clear Aβ. The GAS, as a targeting detector and inhibitor, allows real-time detection of Aβ aggregates. : These results firstly highlight the combination of , APH and nanoparticles to be theranostic AD drugs. Taken together, our strategy provides a new thought into the design of smart compounds for use as efficiently therapeutic and preventive agents against AD. Moreover, our design provides broad prospects of biomedical strategy for further theranostics application in those diseases caused by abnormal protein.
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http://dx.doi.org/10.7150/thno.30649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531298PMC
June 2020

Multiple Antigenic Peptide System Coupled with Amyloid Beta Protein Epitopes As An Immunization Approach to Treat Alzheimer's Disease.

ACS Chem Neurosci 2019 06 10;10(6):2794-2800. Epub 2019 May 10.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences , Jilin University , Changchun , Jilin 130012 , China.

Latest studies suggest that Alzheimer's disease (AD) is one of the "four big killers" that threaten the health of the elderly. AD affects about 46 million people across the world, and there is a critical need for research on new therapies for treating AD. The purpose of the present study was to develop and evaluate immunogens to elicit antibodies against the formation of amyloid beta protein (Aβ), a pathological hallmark of AD, as a therapeutic strategy in AD. In this study, serial potential immunogenic epitopes were screened according to the Aβ sequence. The screened linear epitopes on the Aβ C-terminal fragment were coupled with either the carrier protein keyhole limpet hemocyanin (KLH) or the synthesized 4-branch peptide (MAP). MAP immunogens could effectively elicit immunogenicity against Aβ monomer and fiber in Balb/C mice. Furthermore, MAP sera could also effectively inhibit the formation of the Aβ fiber. Interestingly, one of the MAP sera was able to depolymerize the Aβ fibers that had aggregated. The monoclonal antibody, 1H7, was shown to inhibit the formation of Aβ fiber. MAP carrier may provide benefits over current immunization strategies, as it does not induce inflammation. In conclusion, the MAP-Aβ conjugates offer a promising approach for the development of a safe and effective AD vaccine.
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http://dx.doi.org/10.1021/acschemneuro.9b00020DOI Listing
June 2019

Effects of Tyr555 and Trp678 on the processivity of cellobiohydrolase A from Ruminiclostridium thermocellum: A simulation study.

Biopolymers 2018 Dec 28;109(12):e23238. Epub 2018 Nov 28.

Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, China.

Cellobiohydrolase A from Ruminiclostridium thermocellum (Cbh9A) is a processive exoglucanase from family 9 and is an important cellobiohydrolase that hydrolyzes cello-oligosaccharide into cellobiose. Residues Tyr555 and Trp678 considerably affect catalytic activity, but their mechanisms are still unknown. To investigate how the Tyr555 and Trp678 affect the processivity of Cbh9A, conventional molecular dynamics, steered molecular dynamics, and free energy calculation were performed to simulate the processive process of wild type (WT)-Cbh9A, Y555S mutant, and W678G mutant. Analysis of simulation results suggests that the binding free energies between the substrate and WT-Cbh9A are lower than those of Y555S and W678G mutants. The pull forces and energy barrier in Y555S and W678G mutants also reduced significantly during the steered molecular dynamics (SMD) simulation compared with that of the WT-Cbh9A. And the potential mean force calculations showed that the pulling energy barrier of Y555S and W678G mutants is much lower than that of WT-Cbh9A.
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http://dx.doi.org/10.1002/bip.23238DOI Listing
December 2018

Screening and expressing HIV-1 specific antibody fragments in Saccharomyces cerevisiae.

Mol Immunol 2018 11 17;103:279-285. Epub 2018 Oct 17.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China; Institute of Translational Medicine, Faculty of Heath Sciences, University of Macau, Macau, China. Electronic address:

Yeast displaying techniques have been widely used for identifying novel single-chain variable fragments (scFvs) and engineering their binding properties. In this study, we establish a set of vectors for scFv screening and production in the yeast system of Saccharomyces cerevisiae. This suite includes a display vector pYS for screening of recombinant scFv libraries as well as an expression vector pYE for production of scFv candidates in Saccharomyces cerevisiae. The display vector, pYS, give the identification of the HIV-1-specific scFv clones from one scFv display library by fluorescence-activated cell sorting. Subsequently, the expression vector pYE can offer high quality scFvs of interest up to hundreds of microgram scale for bioactivity analysis. As the result, one identified scFv was confirmed to exhibit HIV-1 neutralization activity in a cell line-based pseudovirus assay. The advantage of this system enables the identical post-translation of mammalian scFvs in the same host cells. Therefore, this vector set can be useful for the rapid screening and expression of antibody genes.
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http://dx.doi.org/10.1016/j.molimm.2018.10.013DOI Listing
November 2018

A dual-specific IGF-I/II human engineered antibody domain inhibits IGF signaling in breast cancer cells.

Int J Biol Sci 2018 21;14(7):799-806. Epub 2018 May 21.

Faculty of Health Sciences, University of Macau, Macau, China.

The insulin-like growth factors (IGFs), IGF-I and IGF-II, are essential for regulating cell growth, differentiation and metastasis of a broad range of malignancies. The IGF-I/II actions are mediated through the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR), which are overexpressed in multiple types of tumors. Here, we have firstly identified a human engineered antibody domain (eAd) from a phage-displayed VH library. The eAd suppressed the signal transduction of IGF-1R mediated by exogenous IGF-I or IGF-II in breast cancer cell lines through neutralizing both IGF-I and IGF-II. It also significantly inhibited the growth of breast cancer cells. Therefore, the anti-IGF-I/II eAd offers an alternative approach to target both the IGF-1R signaling pathways through the inhibition of IGF-I/II.
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http://dx.doi.org/10.7150/ijbs.25928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001679PMC
July 2019

Humanization and directed evolution of the selenium-containing phage abzyme.

RSC Adv 2018 May 10;8(31):17218-17223. Epub 2018 May 10.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University Changchun Jilin China +86 431 85167751 +86 431 89228979.

According to the binding site structure and the catalytic mechanism of the native glutathione peroxidase (GPX), three glutathione derivatives, GSH-S-DNP butyl ester (hapten Be), GSH-S-DNP hexyl ester (hapten He) and GSH-S-DNP hexamethylene ester (hapten Hme) were synthesized. By a four-round panning with a human synthetic phage library against three haptens, the enrichment of the phage particles with specific binding activity could be determined. Three phage particles were selected binding to each glutathione derivative, respectively. After a two-step chemical mutation to convert the serine residues of the phage particles into selenocysteine residues, GPX activity could be observed and determined upto 3000 U μmol in the selenium-containing phage abzyme which was isolated by affinity capture against the hapten Be. Also the phage abzymes elicited by different antigens displayed different catalytic activities. After a directed evolution by DNA shuffling to improve the affinity to the hapten Be, a secondary library with GPX activity was created in which the catalytic activity of the selenium-containing phage abzyme could be increased 17%. This study might be helpful for new haptens or antigens design to optimize the abzymes with high binding activities and might also provide a novel scheme for GPX mimic candidates for drug development.
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http://dx.doi.org/10.1039/c8ra02798fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9080455PMC
May 2018

Insight into the process of product expulsion in cellobiohydrolase Cel6A from Trichoderma reesei by computational modeling.

J Biomol Struct Dyn 2019 Mar 24;37(5):1360-1374. Epub 2018 Mar 24.

a Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , People's Republic of China.

Glycoside hydrolase cellulase family 6 from Trichoderma reesei (TrCel6A) is an important cellobiohydrolase to hydrolyze cellooligosaccharide into cellobiose. The knowledge of enzymatic mechanisms is critical for improving the conversion efficiency of cellulose into ethanol or other chemicals. However, the process of product expulsion, a key component of enzymatic depolymerization, from TrCel6A has not yet been described in detail. Here, conventional molecular dynamics and steered molecular dynamics (SMD) were applied to study product expulsion from TrCel6A. Tyr103 may be a crucial residue in product expulsion given that it exhibits two different posthydrolytic conformations. In one conformation, Tyr103 rotates to open the -3 subsite. However, Tyr103 does not rotate in the other conformation. Three different routes for product expulsion were proposed on the basis of the two different conformations. The total energy barriers of the three routes were calculated through SMD simulations. The total energy barrier of product expulsion through Route 1, in which Tyr103 does not rotate, was 22.2 kcal·mol. The total energy barriers of product expulsion through Routes 2 and 3, in which Tyr103 rotates to open the -3 subsite, were 10.3 and 14.4 kcal·mol, respectively. Therefore, Routes 2 and 3 have lower energy barriers than Route 1, and Route 2 is the thermodynamically optimal route for product expulsion. Consequently, the rotation of Tyr103 may be crucial for product release from TrCel6A. Results of this work have potential applications in cellulase engineering.
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http://dx.doi.org/10.1080/07391102.2018.1450164DOI Listing
March 2019

Effects of insulin on transcriptional response and permeability in an in vitro model of human blood-brain barrier.

J Cell Biochem 2018 07 12;119(7):5657-5664. Epub 2018 Mar 12.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. Active and passive immune therapies targeting beta amyloid (Aβ) have shown very limited evidence in human studies of clinical benefits from these approaches. Epidemiological studies have shown that subjects with type 2 diabetes (T2D) are at higher risk of developing AD. However, whether and how these two conditions are causally linked is unknown. With the purpose of confirming the relationship between T2D and AD, this study specifically focused on effects of insulin in an in vitro model of the human blood-brain barrier (BBB) and on potential mechanisms of action in the treatment of AD. By using a series of assays to establish a BBB model, we demonstrated that insulin treatment alone could induce the increase of brain endothelial barrier properties. The transcriptional response of hCMEC/D3 cells to activation with different concentrations of insulin was determined by RT-PCR, and expression levels of genes involved in the control of barrier permeability, including inter-brain endothelial junctions, integrin-focal adhesions complexes, and transporter system, were found to be altered by the treatment. Notably, the influence of insulin on expression of the ATP-binding cassette (ABC) transporter which contributes to the clearance of Aβ was investigated. Insulin up-regulated adherens junction and tight junction transmembrane proteins, as well as the ABC transporter. By treatment with insulin, the models have major advantages: it is fast, it has low cost, it is fit for considerable samples, and its conditions are under control.
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http://dx.doi.org/10.1002/jcb.26744DOI Listing
July 2018

A novel small molecule displays two different binding modes during inhibiting H1N1 influenza A virus neuraminidases.

J Struct Biol 2018 05 28;202(2):142-149. Epub 2017 Dec 28.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin 130012, China; Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin 30012, China. Electronic address:

Neuraminidase (NA) inhibitors can suppress NA activity to block the release of progeny virions and are effective against influenza viruses. As potential anti-flu drugs with unique functions, NA inhibitors are greatly concerned by the worldwide scientists. It has been reported recently that one of the novel quindoline derivatives named 7a, could inhibit both A/Puerto Rico/8/34 (H1N1) NA (NA) and A/California/04/09 (H1N1) NA (NA). However, potential structure differences in the active site could be easily detected between the NA and NA according to the flexibilities of their 150-loops located catalytic site. And no obvious 150-cavity could be observed in NA crystal structure. In order to explore whether 7a could trigger the inhibition against these two NAs in the same way, a serial molecular dynamics simulation approach were applied in this study. The results indicated that 7a could be adopted under a relatively extended pose in the active center of NA. While in NA-7a complex, the derivate preferred to be recognized and located on the side of active center. Interestingly, the potential of 7a was also found to be able to change the flexibility of the 150-loop in NA that is absent of 150-cavity. Furthermore, a 150-cavity-like architecture could be induced in the active site of NA. The results of this study revealed two kinds of binding modes of this novel small molecule inhibitor against NAs that might provide a theoretical basis for proposing novel inhibition mechanism and developing future influenza A virus inhibitors.
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http://dx.doi.org/10.1016/j.jsb.2017.12.014DOI Listing
May 2018

Effects of poly(I:C) and MF59 co-adjuvants on immunogenicity and efficacy of survivin polypeptide immunogen against melanoma.

J Cell Physiol 2018 06 29;233(6):4926-4934. Epub 2017 Dec 29.

Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, Jilin, China.

Malignant tumors pose a public health problem that jeopardizes human life and quality of living. At present, tumor vaccines in clinical research typically are aimed at stimulating the cellular immune response, while more effective vaccines should take into account the synergy between broad spectrum antibodies and high levels of cellular immunity. In this study, epitope peptides (68-81, 95-104, 80-88) of the tumor antigen survivin were chosen as immunogens and supplemented with poly(I:C) and/or MF59 adjuvant to evaluate the immune effects and anti-melanoma activities. The results indicated that poly(I:C) and MF59 could assist the survivin epitope peptide immunogen to control the tumor size, quality, and volume in black melanoma mouse models. Analyses by antibody titering, antibody isotyping and ELISPOT suggested that the adjuvanted immunogen could induce humoral immunity in mice. Poly(I:C) and MF59 combined with survivin peptide 95-104 could effectively induce humoral immunity mediated by type 2 T helper (Th2) cells. This study provides a basis for candidate immunogen design based on survivin and provides support for tumor therapy that can induce a more balanced Th1/Th2 immune response.
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http://dx.doi.org/10.1002/jcp.26317DOI Listing
June 2018

Screening HCV genotype-specific epitope peptides based on conserved sequence analysis and B cell epitope prediction in HCV E2 region.

Immunol Res 2018 02;66(1):67-73

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.

The high mutation rate of the hepatitis C virus (HCV) genome increases the genotype diversity and renders the detection of the virus more difficult. Therefore, prediction and assessment of highly conserved and strongly antigenic epitope polypeptide sequences have become a focus of current research. The E2 region is the target binding region of neutralizing antibodies. HCV genomics, especially the high mutation rate of E2 region sequence, makes its genotyping more and more diverse, and the detection of HCV and genotype is becoming more and more strict. In this study, four HCV B cell epitope polypeptides were constructed based on assessment of conserved sequences in the HCV E2 region and prediction of B cell epitopes, including sequences specific to genotype 1A (DC-13: 434-DTGWLAGLFYYHK-446), genotype 1B (HC-13: 434-HTGFLAALFYAKS-446), genotype 4D (NC-13: 434-NTGFLASLFYTHK-446), and a consensus sequence (FC-9: 447-FNSSGCPER-455). Epitope polypeptides combined with serum from 29 HCV-infected or 25 non-HCV-infected individuals were assayed by enzyme-linked immunosorbent assay (ELISA), and differences were analyzed by T/T' test methods in SPSS v20.0 software. Binding levels of genotype 1A, 4D, and consensus epitope polypeptides with sera of HCV-infected patients were higher than those of non-infected individuals. Moreover, binding of genotype 1B epitope polypeptides with serum of HCV 1B-infected patients was higher than that of HCV 2A-infected patients. While the screening results of HCV genotype-specific epitope polypeptides were preliminary, these findings indicated that we successfully established an HCV and genotype serological ELISA detection method. Such an approach would facilitate the discovery of epitope polypeptides which may become new antigen candidates in peptide vaccine development for the prevention of HCV infection.
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http://dx.doi.org/10.1007/s12026-017-8962-7DOI Listing
February 2018

Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation.

Sci Rep 2017 06 19;7(1):3786. Epub 2017 Jun 19.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.

Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors.
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http://dx.doi.org/10.1038/s41598-017-03719-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476670PMC
June 2017

A novel "turn-on" thiooxofluorescein-based colorimetric and fluorescent sensor for Hg and its application in living cells.

Talanta 2017 Aug 31;170:103-110. Epub 2017 Mar 31.

College of Chemistry, Jilin University, Changchun 130021, PR China.

A novel water-soluble fluorescent probe FLS2 based on the thiooxofluorescein derivative has been firstly designed and synthesized. UV-vis absorption and fluorescence spectra studies showed that the FLS2 as a colorimetric and ratiometric fluorescent probe exhibited high selectivity and sensitivity towards Hg, which was mainly attributed to the special binding with the receptor unit accompanied with the spirolactam ring-opening progress. In addition, the probe FLS2 could be used as a naked-eye indicator for Hg with reversible response. It displayed approximate 37-fold fluorescent enhancement at 529nm in the presence of only 2.0 equiv. Hg and the detection limit was calculated at about 39nM. What's more, cellular imaging experiment revealed that the sensor had excellent biocompatibility and low cytotoxicity that could be utilized for monitoring Hg in living cells.
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http://dx.doi.org/10.1016/j.talanta.2017.03.099DOI Listing
August 2017

Inducing Polyclonal Eag1-Specific Antibodies by Vaccination with a Linear Epitope Immunogen and Its Relation to Breast Tumorigenesis.

Pathol Oncol Res 2017 Oct 9;23(4):761-767. Epub 2017 Jan 9.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, People's Republic of China.

Ether à-go-go 1 (KCNH1, Kv10.1) (Eag1) is a voltage-gated potassium channel, which is commonly overexpressed in tested breast cancer patients. This occurrence makes it a potential molecular marker and a promising tool for breast cancer diagnosis and therapy. In order to explore protective or specific polyclonal antibodies for further research, potential linear epitopes from Eag1 were collected by sequence alignment. The sequence was synthesized and then coupled to the carrier protein keyhole limpet hemocyanin (KLH) for animal immunization. Polyclonal antibodies against Eag1 were produced and purified from the rabbit antisera. Enzyme linked immunosorbent assay (ELISA) and western blot were performed to characterize their specificities. Immunohistochemical staining was carried out on normal and cancerous breast tissue sections using the purified polyclonal Eag1-specific antibodies. The results indicate that the overexpression of Eag1 might be associated with an increased risk of progression to breast cancer (Grade 1 tissue = 57.89%;Grade 2 tissue = 92.59%;Grade 3 tissue = 100%). These results also suggest that Eag1 gene is a putative growth-promoting gene that might be involved in breast tumorigenesis and development. Eag1 might further be represented as a potential target for some human diseases treatment.
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http://dx.doi.org/10.1007/s12253-016-0158-2DOI Listing
October 2017

Eliciting 10E8-like antibodies by the membrane proximal external region peptide of HIV-1 in guinea pigs.

Biotechnol Lett 2017 Mar 10;39(3):367-373. Epub 2016 Dec 10.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, No. 2699 Qianjin Street, Changchun, 130012, Jilin, China.

Objective: To develop an immunotherapy for HIV that can elicit 10E8-like broadly-neutralizing antibodies in guinea pigs, using a multiple antigen peptide (MAP) system as the platform and 10E8 peptide as the epitope.

Results: The immunogen, 10E8-MAP, was synthetized using the MAP system. The synthetic 10E8-MAP was stable, and the epitopes could be exposed for recognition. In addition, the 10E8 epitope was present in an α-helical structure, which was hypothesized to aid in the generation of neutralizing antibodies. In vivo analysis showed that 10E8-MAP could efficiently elicit HIV binding antibodies in guinea pigs, although only weak neutralizing activities were observed.

Conclusions: Multiple antigen peptide is an excellent vaccine platform for generating binding antibodies, but may elicit weak neutralizing antibodies for HIV.
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http://dx.doi.org/10.1007/s10529-016-2267-0DOI Listing
March 2017

Expression of HIV-1 broadly neutralizing antibodies mediated by recombinant adeno-associated virus 8 in vitro and in vivo.

Mol Immunol 2016 12 12;80:68-77. Epub 2016 Nov 12.

National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, Jilin, China; Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, Jilin, China. Electronic address:

Despite unremitting efforts since the discovery of human immunodeficiency virus type 1 (HIV-1), an effective vaccine has not been generated. Viral vector-mediated transfer for expression of HIV-1 broadly neutralizing antibodies (BnAbs) is an attractive strategy. In this study, a recombinant adeno-associated virus 8 (rAAV8) vector was used to encode full-length antibodies against HIV-1 in 293T cells and Balb/c mice after gene transfer. The 10E8 or NIH45-46 BnAb was expressed from a single open reading frame by linking the heavy and light chains with a furin cleavage and a 2A self-processing peptide (F2A). The results showed that the BnAbs could be expressed in the 293T cell culture medium. A single intramuscular injection of rAAV8 led to long-term expression of BnAbs in Balb/c mice. The expressed antibodies in the supernatant of 293T cells and in Balb/c mice showed neutralization effects against HIV-1 pseudoviruses. Combined immunization of rAAV8 expressing 10E8 and rAAV8 expressing NIH45-46 in Balb/c mice could increase these neutralization effects on strains of HIV-1 sensitive to 10E8 or NIH45-46 antibody compared with a single injection of rAAV8 expressing either antibody alone. Therefore, the combined immunization may be a potential vaccine approach against HIV-1.
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http://dx.doi.org/10.1016/j.molimm.2016.10.011DOI Listing
December 2016
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