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Optimal Timing of Antiretroviral Therapy Initiation in Acquired Immunodeficiency Syndrome-Associated Toxoplasmic Encephalitis:A Prospective Observational Multicenter Study in china

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infectious diseases & Immunity 2024年第1期4卷 4-9页

作者： Yao Li Haidong Jiang Yanming Zeng Yanqiu Lu Siyuan Chen Yulin Zhang Zhongsheng Jiang Tongtong Yang Shuiqing Liu Yaokai Chen Department of infectious diseases Chongqing Public Health Medical CenterChongqing 400036China center for infectious diseases Beijing Youan HospitalCapital Medical UniversityBeijing 100069China Department of infectious diseases Liuzhou People's HospitalLiuzhou 545006GuangxiChina Department of infectious Disease The Public Health Clinical Center of ChengduChengdu 610066SichuanChina Department of infectious Disease Guiyang Public Health Clinical CenterGuiyang 550004GuizhouChina

Background:Toxoplasmic encephalitis(TE)is the most frequent cause of expansive brain lesions among patients with acquired immunodeficiency syndrome(AIDS).However,the optimal timing of antiretroviral therapy(ART)initiation in these patients remains controversial.This study aims to investigate the differences in outcomes of ART initiation at different times,in order to help clarify the treatment timing of AIDS-associated TE.Methods:This multicenter prospective observational study included 87 patients recruited from 11 research centers in china(from March 2019 to December 2022).Of the patients,38 were assigned to the early ART group(initiating ART within 2 weeks after anti-Toxoplasma treatment initiation),and the remaining 49 patients received deferred ART(initiating ART at least 2 weeks after anti-Toxoplasma treatment initiation).The main outcomes includedmortality and emergence of immune reconstitution inflammatory syndrome(IRIS).Human immunodeficiency virus(HIV)-1 viral load and CD4^(+)T-cell counts at weeks 24 and 48 were observed.Results:The number of deaths(1 vs.5,P=0.225)and incidence of IRIS(2.6%vs.0,P=0.437)were not significantly different between the early and deferred ART groups at week 48.Early ART initiation did not contribute significantly to HIV-1 viral load control(<50 copies/mL,n=8 vs.n=3 at week 24,P=0.142;n=7 vs.n=7 atweek 48,P=1.000).The median CD4^(+)T-cell counts between the two groups were not significantly different,either at week 24(155 vs.91 cells/mm^(3),P=0.837)or atweek 48(181 vs.146 cells/mm^(3),P=0.219).Conclusion:In patients with AIDS-associated TE,early ART initiation was not significantly different from deferred ART initiation in terms of incidence of mortality,IRIS,and HIV virological and immunological outcomes.Trial registration:This study was registered(registration number:ChiCTR1900021195)as one of 12 clinical trials under the title of a general project at the Chinese Clinical Trial Registry(chictr.gov)on February 1,2019.Enrollment for this study began inMarch 2019.

关键词： HIV Toxoplasma gondii Timing of antiretroviral therapy Virological outcome Immunological response

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Phosphorylation of PB2 at serine 181 restricts viral replication and virulence of the highly pathogenic H5N1 avian influenza virus in mice

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Virologica Sinica 2024年第1期39卷 97-112页

作者： Jiao Hu Zixiong Zeng Xia Chen Manyu Zhang Zenglei Hu Min Gu Xiaoquan Wang Ruyi Gao Shunlin Hu Yu Chen Xiaowen Liu Daxin Peng Xiufan Liu Animal infectious Disease Laboratory School of Veterinary MedicineYangzhou UniversityYangzhou225009China joint International research Laboratory of Agriculture and Agri-Product Safety The Ministry of Education of ChinaYangzhou University225009China Jiangsu Co-Innovation center for Prevention and Control of Important Animal infectious diseases and Zoonosis Yangzhou UniversityYangzhou225009China Key Laboratory of Prevention and Control of Biological Hazard Factors(Animal Origin)for Agri-food Safety and Quality Ministry of Agriculture of China(26116120)Yangzhou UniversityYangzhou225009China

Influenza A virus(IAV)continues to pose a pandemic threat to public health,resulting a high mortality rate annually and during pandemic years.Posttranslational modification of viral protein plays a substantial role in regulating IAV infection.Here,based on immunoprecipitation(IP)-based mass spectrometry(MS)and purified virus-coupled MS,a total of 89 phosphorylation sites distributed among 10 encoded viral proteins of IAV were identified,including 60 novel phosphorylation sites.Additionally,for the first time,we provide evidence that PB2 can also be acetylated at site K187.Notably,the PB2 S181 phosphorylation site was consistently identified in both IP-based MS and purified virus-based MS.Both S181 and K187 are exposed on the surface of the PB2 protein and are highly conserved in various IAV strains,suggesting their fundamental importance in the IAV life cycle.Bioinformatic analysis results demonstrated that S181E/A and K187Q/R mimic mutations do not significantly alter the PB2 protein structure.While continuous phosphorylation mimicked by the PB2 S181E mutation substantially decreases viral fitness in mice,PB2 K187Q mimetic acetylation slightly enhances viral virulence in mice.Mechanistically,PB2 S181E substantially impairs viral polymerase activity and viral replication,remarkably dampens protein stability and nuclear accumulation of PB2,and significantly weakens IAV-induced inflammatory responses.Therefore,our study further enriches the database of phosphorylation and acetylation sites of influenza viral proteins,laying a foundation for subsequent mechanistic studies.Meanwhile,the unraveled antiviral effect of PB2 S181E mimetic phosphorylation may provide a new target for the subsequent study of antiviral drugs.

关键词： H5N1 influenza virus PB2 Phosphorylation Acetylation Viral fitness Mice

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Plasma Metabonomics of Human Adenovirus-infected Patients with Pneumonia and Upper Respiratory Tract Infection

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Current Medical Science 2024年第1期44卷 121-133页

作者： Ting-ting WEI Wen XU Bo TU Wan-xue ZHANG Xin-xin YANG Yiguo ZHOU Shan-shan ZHANG Jun-lian YANG Ming-zhu XIE Juan DU Wei-wei CHEN Qing-bin LU Department of Epidemiology and Biostatistics School of Public HealthPeking UniversityBeijing 100191China Department of infectious Disease The Fifth Medical Center of Chinese PLA General HospitalNational Clinical Research Center for Infectious DiseasesBeijing 100039China Department of Laboratorial Science and Technology&Vaccine research center School of Public HealthPeking UniversityBeijing 100191China Department of Health Policy and Management School of Public HealthPeking UniversityBeijing 100191China Global center for infectious Disease and Policy research&Global Health and infectious diseases Group Peking UniversityBeijing 100191China Key Laboratory of Epidemiology of Major diseases(Peking University) Ministry of EducationBeijing 100191China

Objective Human adenovirus(HAdV)infection is common and can develop to serious conditions with high mortality,yet the mechanism of HAdV infection remains unclear.In the present study,the serum metabolite profiles of HAdV-7-infected patients with pneumonia or upper respiratory tract infection(URTI)were explored.Methods In total,35 patients were enrolled in the study following an outbreak of HAdV-7 in the army,of whom 14 had pneumonia and 21 had URTI.Blood samples were collected at the acute stage and at the recovery stage and were analyzed by untargeted metabolomics.Results Over 90% of the differential metabolites identified between the pneumonia patients and URTI patients were lipids and lipid-like molecules,including glycerophospholipids,fatty acyls,and sphingolipids.The metabolic pathways that were significantly enriched were primarily the lipid metabolism pathways,including sphingolipid metabolism,glycerophospholipid metabolism,and linoleic acid metabolism.The sphingolipid metabolism was identified as a significantly differential pathway between the pneumonia patients and URTI patients and between the acute and recovery stages for the pneumonia patients,but not between the acute and recovery stages for the URTI patients.Ceramide and lactosylceramide,involved in sphingolipid metabolism,were significantly higher in the pneumonia patients than in the URTI patients with good discrimination abilities[area under curve(AUC)0.742 and 0.716,respectively;combination AUC 0.801].Conclusion Our results suggested that HAdV modulated lipid metabolism for both the patients with URTI and pneumonia,especially the sphingolipid metabolism involving ceramide and lactosylceramide,which might thus be a potential intervention target in the treatment of HAdV infection.

关键词： human adenovirus metabonomic lipids pneumonia upper respiratory tract infection

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Identification of novel mammalian viruses in tree shrews(Tupaia belangeri chinensis)

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Zoological research 2024年第2期45卷 429-438页

作者： Hong Zhou Ren-Rong Tian Xiu-Rong Wang Jin-Xuan Yang Yun-Xiao Wang Ming-Liang Zhao Xu-Dong Zhang Yu-Hua Ma Long-Bao Lv Edward CHolmes Yong-Tang Zheng Wei-Feng Shi School of Clinical and Basic Medical Sciences Shandong First Medical University&Shandong Academy of Medical SciencesJi’nanShandong 250117China Key Laboratory of Emerging infectious diseases in Universities of Shandong Shandong First Medical University and Shandong Academy of Medical SciencesTaianShandong 271000China Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesCenter for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China School of Public Health Shandong First Medical University&Shandong Academy of Medical SciencesJi’nanShandong 250117China National Resource center for Non-Human Primates Kunming Primate Research CenterKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China Sydney Institute for infectious diseases School of Medical SciencesThe University of SydneySydneyNew South Wales 2006Australia Department of infectious diseases Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Institute of Virology Shanghai Jiao Tong University School of MedicineShanghai 200025China

The Chinese tree shrew(Tupaia belangeri chinensis),a member of the mammalian order Scandentia,exhibits considerable similarities with primates,including humans,in aspects of its nervous,immune,and metabolic systems.These similarities have established the tree shrew as a promising experimental model for biomedical research on cancer,infectious diseases,metabolic disorders,and mental health conditions.Herein,we used metatranscriptomic sequencing to analyze plasma,as well as oral and anal swab samples,from 105 healthy asymptomatic tree shrews to identify the presence of potential zoonotic viruses.In total,eight mammalian viruses with complete genomes were identified,belonging to six viral families,including Flaviviridae,Hepeviridae,Parvovirinae,Picornaviridae,Sedoreoviridae,and Spinareoviridae.Notably,the presence of rotavirus was recorded in tree shrews for the first time.Three viruses-hepacivirus 1,parvovirus,and picornavirus-exhibited low genetic similarity(94%)to known viral strains.Phylogenetic analyses also revealed that the rotavirus and mammalian orthoreovirus identified in this study may be novel reassortants.These findings provide insights into the diverse viral spectrum present in captive Chinese tree shrews,highlighting the necessity for further research into their potential for crossspecies transmission.

关键词： Tree shrew(Tupaia belangeri chinensis) Meta-transcriptomic sequencing Mammalian viruses Genomic analysis

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Antibodies elicited by Newcastle disease virus-vectored H7N9 avian influenza vaccine are functional in activating the complement system

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Journal of Integrative Agriculture 2024年第6期23卷 2052-2064页

作者： Zenglei Hu Ya Huang Jiao Hu Xiaoquan Wang Shunlin Hu Xiufan Liu joint International research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of china Yangzhou UniversityYangzhou 225009China Animal infectious Disease Laboratory School of Veterinary MedicineYangzhou UniversityYangzhou 225009China Jiangsu Co-innovation center for Prevention and Control of Important Animal infectious diseases and Zoonoses Yangzhou UniversityYangzhou 225009China

H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are protective and allow mass administration.Of note,these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition(HI)but high IgG antibodies in chickens.However,the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear.Herein,immunization with an NDV_(vec)H7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin(HA)-binding IgG antibodies in chickens.Three residues(S150,G151 and S152)in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_(vec)H7N9 immune serum.Passively transferred NDV_(vec)H7N9 immune serum conferred complete protection against H7N9 virus infection in chickens.The NDV_(vec)H7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity.These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor,suggesting the engagement of the complement system.Moreover,mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_(vec)H7N9 immune serum,indicating the requirement of antibody-antigen binding for complement activity.Therefore,antibodies induced by the NDV_(vec)H7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus.Our findings unveiled a novel role of the complement in protection conferred by the NDV_(vec)H7N9,highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.

关键词： H7N9 subtype avian influenza virus NDV vector vaccine antibody immunity complement protection

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Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115

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Cellular & Molecular Immunology 2024年第3期21卷 275-291页

作者： Zhi-Dong Zhang Chang-Rui Shi Fang-Xu Li Hu Gan Yanhong Wei Qianhui Zhang Xin Shuai Min Chen Yu-Lin Lin Tian-Chen Xiong Xiaoqi Chen Bo Zhong Dandan Lin Department of Gastrointestinal Surgery Medical Research InstituteFrontier Science Center of Immunology and MetabolismZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan430071China Department of Virology College of Life SciencesWuhan UniversityWuhan430072China TaiKang center for Life and Medical Sciences Wuhan UniversityWuhan430071China Wuhan research center for infectious diseases and Cancer Chinese Academy of Medical SciencesWuhan430071China Department of Rheumatology and Immunology Zhongnan Hospital of Wuhan UniversityWuhan430071China Cancer center Renmin Hospital of Wuhan UniversityWuhan430060China

STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation.Here,we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram(DSF).Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1^(–/–)mice and STING^(N153S/WT) bone marrow chimeric mice.In addition,knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α,IFN-γand proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus(SLE)who exhibit high concentrations of dsDNA in peripheral blood.Mechanistically,knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1^(–/–)mice.Interestingly,knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts.Taken together,these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.

关键词： STING/MITA Disulfiram RNF115 SLE Autoimmunity

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Effects of COVID-19 pandemic on human fertility:A scientometric and visualized evaluation

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Genes & diseases 2024年第4期11卷 113-115页

作者： Xiangxiu Wang Yifan Rao Lili Tan Ziqiu Hu Lin Wen Weixi Qin Bingyi Li Keqiao He Tieying Yin Juhui Qiu Yuming Wang Yaokai Chen Xiancai Rao Guixue Wang Key Laboratory of Biorheological and Technology of the Ministry of Education State and Local Joint Engineering LaboratoryforVascular ImplantsModern LifeScience Experiment Teaching Center at Bioengineering College of Chongqing UniversityChongqing 400030China Department of Microbiology College of Basic Medical SciencesKey Laboratory of Microbial Engineering Under the Educational Committee in ChongqingArmy Medical University(Third Military Medical University)Chongqing 400038China Jinfeng Laboratory Chongqing 401329China Division of infectious diseases Chongqing Public Health Medical CenterChongqing 400036China

CovID-19,also known as coronavirus disease 2019,is a novel coronavirus disease with high infectivity,strong heterogeneity,and long incubation period(generally 3-14 days).Its main symptoms and signs include fever,dry cough,nasal congestion,fatigue,disorientation,lymphopenia,and dyspnea.The short-term and long-term impacts of covID-19 on human health,particularly its effects on human reproduction and offspring development,continue to receive significant concerns,as they may lead to potential sequelae for several decades or even centuries.

关键词： nasal fertility fever

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Inhibition of hepatitis B virus via selective apoptosis modulation by Chinese patent medicine Liuweiwuling Tablet

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World Journal of Gastroenterology 2024年第13期30卷 1911-1925页

作者： Fei-Lin Ge Yan Yang Lan-Lan Si Yuan-Hua Li Meng-Zhen Cao Jun Wang Zhao-Fang Bai Zhi-Gang Ren Xiao-He Xiao Yan Liu Department of Chinese Medicine State Key Laboratory of Antiviral DrugsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina The Fifth Medical center of Chinese PLA General Hospital Beijing 100039China College of Traditional Chinese Medicine Chongqing Medical UniversityChongqing 400010China Beijing Key Laboratory of Emerging infectious diseases Peking University Ditan Teaching HospitalBeijing 100015China Department of infectious diseases State Key Laboratory of Antiviral Drugsthe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina

BACKGROUND Liuweiwuling Tablet(LWWL)is a Chinese patent medicine approved for the treatment of chronic inflammation caused by hepatitis B virus(HBV)infection.Previous studies have indicated an anti-HBV effect of LWWL,specifically in terms of antigen inhibition,but the underlying mechanism remains unclear.AIM To investigate the potential mechanism of action of LWWL against HBV.METHODS In vitro experiments utilized three HBV-replicating and three non-HBV-replicating cell lines.The in vivo experiment involved a hydrodynamic injectionmediated mouse model with HBV replication.Transcriptomics and metabolomics were used to investigate the underlying mechanisms of action of LWWL.RESULTS In HepG2.1403F cells,LWWL(0.8 mg/mL)exhibited inhibitory effects on HBV DNA,hepatitis B surface antigen and pregenomic RNA(pgRNA)at rates of 51.36%,24.74%and 50.74%,respectively.The inhibition rates of LWWL(0.8mg/mL)on pgRNA/covalently closed circular DNA in HepG2.1403F,HepG2.2.15 and HepG2.A64 cells were 47.78%,39.51%and 46.74%,respectively.Integration of transcriptomics and metabolomics showed that the anti-HBV effect of LWWL was primarily linked to pathways related to apoptosis(PI3K-AKT,CASP8-CASP3 and P53 pathways).Apoptosis flow analysis revealed that the apoptosis rate in the LWWL-treated group was significantly higher than in the control group(CG)among HBV-replicating cell lines,including HepG2.2.15(2.92%±1.01%vs 6.68%±2.04%,P0.05),L02 cells(5.49%±0.80%vs 5.48%±1.01%,P>0.05)and LX2 cells(6.29%±1.54%vs 6.29%±0.88%,P>0.05).TUNEL staining revealed a significantly higher apoptosis rate in the LWWL-treated group than in the CG in the HBVreplicating mouse model,while no noticeable difference in apoptosis rates between the two groups was observed in the non-HBV-replicating mouse m

关键词： Hepatitis B virus Chinese patent medicine Antiviral activity Antiviral mechanism Selective apoptosis

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Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

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Cellular & Molecular Immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong Lamao Meichao Gu Xuanxuan Jin Ying Liu Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao Thomas S.Fulford Adam P.Uldrich Catherine C.L Wong Wensheng Wei Biomedical Pioneering Innovation center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina center for Precision Medicine Multi-Omics research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity The University of MelbourneParkvilleVIC3010Australia Cancer Immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key Laboratory for Complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell Cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite Immunotherapy

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Flux Balance Analysis Reveals Potential Anti-HIV-1 Metabolic Targets

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infectious diseases & Immunity 2024年第2期4卷 61-68页

作者： Runpeng Han Fei Luo Haisheng Yu Yajun Yan Yan Gong Conghua Xie Liang Cheng Department of Radiation and Medical Oncology Medical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430071China Frontier Science center for Immunology and Metabolism Zhongnan Hospital of Wuhan UniversityState Key Laboratory of VirologyWuhan UniversityWuhan 430071China Guangzhou Eighth People's Hospital Guangzhou Medical UniversityGuangzhou 510440China Department of infectious diseases Zhongnan Hospital of Wuhan UniversityWuhan 430071China Department of Biological Repositories Zhongnan Hospital of Wuhan UniversityWuhan 430071China Wuhan research center for infectious diseases and Cancer Chinese Academy of Medical SciencesWuhan 430071China

Background:Human immunodeficiency virus type 1(HIV-1)remains a persistent global health challenge.Therefore,a continuous exploration of novel therapeutic strategies is essential.A comprehensive understanding of how HIV-1 utilizes the cellular metabolism machinery for replication can provide insights into new therapeutic approaches.Methods:In this study,we performed a flux balance analysis using a genome-scale metabolic model(GEM)integrated with an HIV-1 viral biomass objective function to identify potential targets for anti–HIV-1 interventions.We generated a GEM by integrating an HIV-1 production reaction into CD4+T cells and optimized for both host and virus optimal states as objective functions to depict metabolic profiles of cells in the status for optimal host biomass maintenance or for optimal HIV-1 virion production.Differential analysis was used to predict biochemical reactions altered optimal for HIV-1 production.In addition,we conducted in silico simulations involving gene and reaction knock-outs to identify potential anti–HIV-1 targets,which were subsequently validated by human phytohemagglutinin(PHA)blasts infected with HIV-1.Results:Differential analysis identified several altered biochemical reactions,including increased lysine uptake and oxidative phosphorylation(OXPHOS)activities in the virus optima compared with the host optima.In silico gene and reaction knock-out simulations revealed de novo pyrimidine synthesis,and OXPHOS could serve as potential anti–HIV-1 metabolic targets.In vitro assay confirmed that targeting OXPHOS using metformin could suppress the replication of HIV-1 by 56.6%(385.4±67.5 pg/mL in the metformintreated group vs.888.4±32.3 pg/mL in the control group,P<0.001).Conclusion:Our integrated host-virus genome-scale metabolic study provides insights on potential targets(OXPHOS)for anti-HIV therapies.

关键词： HIV-1 Flux balance analysis Genome-scale metabolic models Viral biomass objective function Therapeutic target

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