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Irreversible phenotypic perturbation and functional impairment of B cells during HIV-1 infection

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Frontiers of Medicine 2017年第4期11卷 536-547页

作者： Jingjing Yan Shuye Zhang Jun Sun jianqing xu Xiaoyang Zhang Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences Fudan University Shanghai 201508 China

Human immunodeficiency virus type 1 （HIV-1） infection can damage humoral immunity. The knowledge of B cell perturbations during chronic HIV-1 infection and their recovery after combined antiretroviral therapy （cART） is not complete yet, and thus attempts to further improve humoral immunity are impeded. In this study, an HIV-1 chronically infected cohort with similar demographics, infection history, genetic background, and HIV-1 genotype was established to probe B cell perturbations. Results showed that the B cells from this cohort were highly activated and prone to cell death, and B cell compartments were altered significantly. Notably, although cART partially reversed the hyperactivation and reduced tissue-like memory B cells, other B cell perturbations, including impaired expression of survival factor Bcl-2, costimulatory molecules, and shrunken resting memory B cells, were irreversible. Further functional characterization revealed that the influenza HA- specific antibody-secreting cells were significantly lower during HIV-1 infection, whereas the recalled antibody response to HIV-l-specific antigens was decreased after cART. Finally, CpG plus R848 treatment increased the survival of B cells and memory B cells in vitro from HIV-l-infected patients. In conclusion, this study identified irreversible B cell immune perturbations in chronic HIV-1 infections regardless of cART and proposed the potential strategy to enhance B cell functions through the improvement of cell survival.

关键词： B cell HIV-1 phenotype functionality antiretroviral therapy

Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway

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Cellular & Molecular Immunology 2017年第6期14卷 529-545页

作者： Rong Wang Aizhang xu xueying Zhang Jie Wu Andrew Freywald jianqing xu Jim Xiang Cancer Research Cluster Saskatchewan Cancer Agency Saskatoon Saskatchewan Canada S7N4H4 School of Public Health University of Saskatchewan Saskatoon Saskatchewan Canada S7N 5E5 Department of Pathology College of Medicine University of Saskatchewan Saskatoon Saskatchewan Canada S7N 5E5 Shanghai Public Health Clinical Center Fudan University Shanghai 201508 China Department of Oncology College of Medicine University of Saskatchewan Saskatoon Saskatchewan Canada S7N 5E5

CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.

关键词： anti-CD40 Ab CD40L signaling chronic infection CTL exhaustion HIV Gag mTORC1 pathway T-cellanergy therapeutic T-cell vaccine

From Monovalent to Multivalent Vaccines, the Exploration for Potential Preventive Strategies Against Hand, Foot, and Mouth Disease(HFMD)

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Virologica Sinica 2021年第2期36卷 167-175页

作者： Xiangchuan He Miaomiao Zhang Chen Zhao Peiyong Zheng Xiaoyan Zhang jianqing xu Shanghai Public Health Clinical Center and Institutes of Biomedical Science Shanghai Medical CollegeFudan UniversityShanghai 201508China Longhua Hospital Shanghai University of Traditional Chinese MedicineShanghai 200032China

Hand,foot,and mouth disease(HFMD)recently emerged as a global public *** licensure of inactivated enterovirus A71(EV-A71)vaccine was the first step in using a vaccine to control *** challenges arise from changes in the pathogen spectrum while vaccines directed against other common serotypes are in the preclinical *** mission of a broad-spectrum prevention strategy clearly favors multivalent *** development of multivalent vaccines was attempted via the simple combination of potent monovalent vaccines or the construction of chimeric vaccines comprised of epitopes derived from different virus *** present review summarizes recent advances in HFMD vaccine development and discusses the next steps toward a safe and effective HFMD vaccine that is capable of establishing a crossprotective antibody response.

关键词： Hand,foot,and mouth disease(HFMD) Inactivated whole virus vaccine Virus-like particles Multivalent vaccines Chimeric vaccines

Freeze-Drying Formulations Increased the Adenovirus and Poxvirus Vaccine Storage Times and Antigen Stabilities

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Virologica Sinica 2021年第3期36卷 365-372页

作者： Ye Chen Qibin Liao Tianyue Chen Yuchao Zhang Weien Yuan jianqing xu Xiaoyan Zhang Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences Fudan UniversityShanghai 201508China Engineering Research Center of Cell and Therapeutic Antibody Ministry of Educationand School of PharmacyShanghai Jiao Tong UniversityShanghai 200000China

Successful vaccines induce specific immune responses and protect against various viral and bacterial infections. Noninactivated vaccines, especially viral vector vaccines such as adenovirus and poxvirus vaccines, dominate the vaccine market because their viral particles are able to replicate and proliferate in vivo and produce lasting immunity in a manner similar to natural infection. One challenge of human and livestock vaccination is vaccine stability related to the antigenicity and infectivity. Freeze-drying is the typical method to maintain virus vaccine stability, while cold chain transportation is required for temperatures about 2 °C–8 °C. The financial and technological resource requirements hinder vaccine distribution in underdeveloped areas. In this study, we developed a freeze-drying formula consisting of bovine serum albumin(BSA), L-glutamic acid(L-Glu), polyethylene glycol(PEG), and dextran(DEX) to improve the thermal stability and activity of viral vaccines, including vaccinia recombinant vaccine(rTTV-OVA) and adenovirus vaccine(Ad5-ENV). We compared a panel of five different formulations(PEG: DEX: BSA: L-GLU = 50:9:0:0(#1), 50:5:4:0(#2), 50:10:9:0(#3),50:0:0:9(#4), and 50:1:0:8(#5), respectively) and optimized the freeze-drying formula for rTTV-OVA and Ad5-ENV. We found that the freeze-drying formulations #2 and #3 could maintain rTTV-OVA infectivity at temperatures of 4 °C and25 °C and that r TTV-OVA immunogenicity was retained during lyophilization. However, formulations #4 and #5 maintained Ad5-ENV infectivity under the same conditions, and Ad5-ENV immunogenicity had maximum retention with freeze-drying formulation #4. In summary, we developed new freeze-drying formulations that increased virus vaccine storage times and retained immunogenicity at an ambient temperature.

关键词： Adenovirus vaccine Poxvirus vaccine Freeze-drying formulation Stability Immunogenicity

A non-human primate derived anti-P-selectin glycoprotein ligand-1 antibody curtails acute pancreatitis by alleviating the inflammatory responses

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4461-4476页

作者： Yuhan Li Xiangqing Ding Xianxian Wu Longfei Ding Yuhui Yang Xiaoliang Jiang Xing Liu xu Zhang Jianrong Su jianqing xu Zhiwei Yang Institute of Laboratory Animal Science Chinese Academy of Medical Sciences(CAMS)&Comparative Medicine CentrePeking Union Medical College(PUMC)Beijing 100021China Department of Clinical Laboratory Beijing Friendship HospitalCapital Medical UniversityBeijing 100050China Shanghai Sinobay Biotechnology Company(Limited) Shanghai 201500China Shanghai Public Health Clinical Center Fudan UniversityShanghai 200083China Capital Medical University Beijing 100069China Department of Hepatobiliary Pancreatic Surgery Zhengzhou University People's HospitalHenan Provincial People's HospitalZhengzhou 450003China Chongqing Institutes for Life Science Innovation Chongqing 400715China

Acute pancreatitis(AP)is a devastating disease characterized by an inflammatory disorder of the pancreas.P-selectin glycoprotein ligand-1(PSGL-1)plays a crucial role in the initial steps of the adhesive at process to inflammatory sites,blockade of PSGL-1 might confer potent anti-inflammatory *** this study,we generated two non-human primate derived monoclonal antibodies capable of efficiently targeting human PSGL-1,RH001-6 and RH001-22,which were screened from immunized rhesus *** found that RH001-6,can effectively block the binding of P-selectin to PSGL-1,and abolish the adhesion of leukocytes to endothelial cells in *** vivo,we verified that RH001-6 relieved inflammatory responses and pancreatic injury in both caerulein and L-arginine induced AP *** also evaluated the safety profile after RH001-6 treatment in mice,and verified that RH001-6 did not cause any significant pathological damages in *** together,we developed a novel non-human primate derived PSGL-1 blocking antibody with high-specificity,named RH001-6,which can interrupt the binding of PSGL-1 and P-selectin and attenuate inflammatory responses during ***,RH001-6 is highly potential to be further developed into therapeutics against acute inflammatory diseases,such as AP.

关键词： Acute pancreatitis PSGL-1 Non-human primate Monoclonal antibody Therapeutic antibody RH001-6 Adhesion of leukocytes to endothelial cells Inflammatory responses Pancreatic injury

Nonmuscle myosin IIA promotes the internalization of influenza A virus and regulates viral polymerase activity through interacting with nucleoprotein in human pulmonary cells

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Virologica Sinica 2023年第1期38卷 128-141页

作者： Jian Chen Jian Liu Zhilu Chen Daobin Feng Cuisong Zhu Jun Fan Shuye Zhang Xiaoyan Zhang jianqing xu Clinical Center for Bio-Therapy Zhongshan HospitalFudan University(Xiamen Branch)Shanghai200032China Center for Infectious Disease Research Science of Life SciencesWestlake UniversityHangzhou310024China Shanghai Public Health Clinical Center&Institutes of Biomedical Sciences Shanghai Medical CollegeFudan UniversityShanghai201508China

Influenza A virus(IAV),responsible for seasonal epidemics and recurring pandemics,represents a global threat to public *** the risk of a potential IAV pandemic,it is increasingly important to better understand virushost interactions and develop new anti-viral ***,we reported nonmuscle myosin IIA(MYH9)-mediated regulation of IAV ***9 depletion caused a profound inhibition of IAV infection by reducing viral attachment and internalization in human lung epithelial ***,overexpression of MYH9 also led to a significant reduction in viral productive ***,overexpression of MYH9 retained viral attachment,internalization,or uncoating,but suppressed the viral ribonucleoprotein(vRNP)activity in a minigenome *** analyses found that excess MYH9 might interrupt the formation of vRNP by interacting with the viral nucleoprotein(NP)and result in the reduction of the completed vRNP in the nucleus,thereby inhibiting subsequent viral RNA transcription and ***,we discovered that MYH9 can interact with IAV NP protein and engage in the regulation of vRNP complexes,thereby involving viral *** findings enlighten new mechanistic insights into the complicated interface of host-IAV interactions,ultimately making it an attractive target for the generation of antiviral drugs.

关键词： Myosin IIA(MYH9) Influenza A virus(IAV) vRNP activity Virus-host interactions Virus entry

Identification of potential cross-protective epitope between a new type of coronavirus(2019-nCoV)and severe acute respiratory syndrome virus

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Journal of Genetics and Genomics 2020年第2期47卷 115-117页

作者： Tianyi Qiu Tiantian Mao Yuan Wang Mengdi Zhou Jingxuan Qiu Jianwei Wang jianqing xu Zhiwei Cao Shanghai Public Health Clinical Center Fudan UniversityShanghai200433China Department of Gastroenterology Shanghai 10th People's HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai200092China NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory IPBCAMS-Fondation MerieuxInstitute of Pathogen Biology(IPB)Chinese Academy of Medical Science&Peking Union Medical CollegeBeijing100730China

Recently,a new type of unknown virus causing severe acute res-piratory infection was reported in Wuhan city,Hubei province,China(WHO,2020b).Infection of this virus was first reported in December 2019,and origin of the virus was traced back to a large seafood/wide animal market in Wuhan *** serious clinical symptoms of the viral infection,including fever,dry cough,dys-pnea,and pneumonia,may result in progressive respiratory failure and even ***,the quick spread of the virus has caused an epidemic in China,as well as infection cases *** whole-genome sequence of Wuhan new virus(WH-Human_.1)was first released on January 10,2020(Zhang,2020),followed by additional ones released in Global Initiative on Sharing All Influ-enza Data(GISAID)(Shu and McCauley,2017).Later,this new virus was determined and announced as a new type of coronavirus(CoV;2019-nCoV)by the World Health Organization(WHO,2020a).

关键词： protective Wuhan acute

Integration of HiBiT into enteroviruses:A universal tool for advancing enterovirus virology research

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Virologica Sinica 2024年第3期39卷 422-433页

作者： Rui Yu Xiaohong Li Peng Zhang Minghao xu Jitong Zhao Jingjing Yan Chenli Qiu Jiayi Shu Shuo Zhang Miaomiao Kang Xiaoyan Zhang jianqing xu Shuye Zhang School of Medicine Shanghai UniversityShanghai200444China Clinical Center for Biotherapy Zhongshan HospitalFudan UniversityShanghai200433China Guangzhou Institutes of Biomedicine and Health The Chinese Academy of SciencesGuangzhou510530China Institutes of Biomedical Sciences Fudan UniversityShanghai200032China Shanghai Geriatric Medical Center Shanghai201104China Clinical Center for Biotherapy Zhongshan Hospital/Zhongshan Hospital(Xiamen)Fudan University361015China Shanghai Public Health Clinical Center Fudan UniversityShanghai201508China

The utilization of enteroviruses engineered with reporter genes serves as a valuable tool for advancing our understanding of enterovirus biology and its applications,enabling the development of effective therapeutic and preventive *** this study,our initial attempts to introduce a NanoLuc luciferase(NLuc)reporter gene into recombinant enteroviruses were unsuccessful in rescuing viable *** hypothesized that the size of the inserted tag might be a determining factor in the rescue of the ***,we inserted the 11-amino-acid HiBiT tag into the genomes of enterovirus A71(EV-A71),coxsackievirus A10(CVA10),coxsackievirus A7(CVA7),coxsackievirus A16(CVA16),namely EV-A71-HiBiT,CVA16-HiBiT,CVA10-HiBiT,CVA7-HiBiT,and observed that the HiBiT-tagged viruses exhibited remarkably high rescue ***,the HiBiT-tagged enteroviruses displayed comparable characteristics to the wild-type viruses.A direct comparison between CVA16-NLuc and CVA16-HiBiT recombinant viruses revealed that the tiny HiBiT insertion had minimal impact on virus infectivity and replication ***,these HiBiT-tagged enteroviruses demonstrated high genetic stability in different cell lines over multiple *** addition,the HiBiT-tagged viruses were successfully tested in antiviral drug assays,and the sensitivity of the viruses to drugs was not affected by the HiBiT ***,our findings provide definitive evidence that the integration of HiBiT into enteroviruses presents a universal,convenient,and invaluable method for advancing research in the realm of enterovirus ***,HiBiT-tagged enteroviruses exhibit great potential for diverse applications,including the development of antivirals and the elucidation of viral infection mechanisms.

关键词： Enterovirus Infectious clones Reporter genes Luciferase Drug screening

Exosomal lncRNA LINC01268 promotes pancreatic cancer progression via the miR-217-KIF2A-PI3K/AKT axis

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Genes & Diseases 2023年第5期10卷 1799-1801页

作者： Shanshan Liu Yang Di Qiuyue Li Litian Chen Yan Ma Xiaomeng He Christopher Corpe Xiaoyan Zhang jianqing xu Jin Wang Shanghai Public Health Clinical Center Fudan UniversityShanghai 201508China Department of Pancreatic Surgery Huashan HospitalFudan UniversityShanghai 201508China Department of Hepatobiliary Surgery Shanghai Jiaotong University School of Medicine Xinhua HospitalShanghai 200025China King's College London LondonNutritional Science DepartmentWaterlooLondon SE19NHUnited Kingdom

Pancreatic cancer(PaCa)is one of the most aggressive and lethal malignancies with rapid progression and poor prognosis with the 5-year survival rate remaining less than 5%because approximately 80%of PaCa patients are diagnosed at an advanced stage and lose the chance of curative resection.1 Accumulated evidence has revealed that noncoding RNAs(ncRNAs)are involved in the pathogenesis of PaCa and serve as potential biomarkers for PaCa.2,3 Exosomal lncRNAs also play a vital role in tumorigenesis and some exosomal lncRNAs have been reported to accelerate tumor progression.4 In this study,we first employed RNA-seq of PaCa plasma samples to identify significantly differentially expressed lncRNAs in PaCa patients and revealed that LINC01268 was up-regulated in PaCa tumor tissues and ***01268 is an emerging lncRNA associated with glioma malignancy grade.5 *** further analyzed the malignant biological behaviors of this lncRNA in PaCa and found that LINC01268 promoted cell proliferation,migration,and invasion as an oncogene,which promoted epithelial–mesenchymal transition(EMT)in PaCa via the miR-217-KIF2A-PI3K/AKT axis.

关键词： PI3K/AKT cancer invasion