PERV病毒在异种移植中的感染风险及预防对策
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摘要
猪与人体在器官结构、生理解剖上相似性高,被认为是最佳的异种移植供体,能够有效解决人类供体器官短缺的问题。猪内源性逆转录病毒(porcine endogenous retrovirus, PERV)是一种C型逆转录病毒,以一种前病毒DNA的形式整合在猪的细胞基因组中,随细胞染色体的复制而复制,无法通过无特定病原体(specific pathogen-free, SPF)培育消除,其在异种移植中具有潜在的感染风险。了解PERV的特性,探索PERV预防策略,将有助于猪作为异种移植供体在临床的应用。
Pigs are considered the best organ donors for xenotransplantation as their organ anatomical struc-tures and physiological functions are similar to humans'. This can effectively help overcome the shortage of human organs for transplantation. The porcine endogenous retrovirus(PERV) belongs to type C retroviruses. It integrates into the genome of pig cells as a provirus and replicates together with the cell chromosomes. As it cannot be excluded from specific pathogen-free breeding colonies, the risk of PERV infection in xenotrans-plantation is potential. To know about the characteristics of PERV and explore its prevention strategy will help us in application of pigs as xenograft donors.
Pigs are considered the best organ donors for xenotransplantation as their organ anatomical struc-tures and physiological functions are similar to humans'. This can effectively help overcome the shortage of human organs for transplantation. The porcine endogenous retrovirus(PERV) belongs to type C retroviruses. It integrates into the genome of pig cells as a provirus and replicates together with the cell chromosomes. As it cannot be excluded from specific pathogen-free breeding colonies, the risk of PERV infection in xenotrans-plantation is potential. To know about the characteristics of PERV and explore its prevention strategy will help us in application of pigs as xenograft donors.
引文
[1]王维,莫朝辉,叶斌,等.新生猪胰岛移植治疗糖尿病病人的临床研究[J].中南大学学报(医学版)(WANG Wei,MO Zhaohui,YE Bin,et al.A clinical trial of xenotransplantation of neonatal pig islets for diabetic patients[J].Journal of Central South University(Medical Sciences)),2011,36(12):1134-1140.
[2]MCGREGOR C G A,BYRNE G W.Porcine to human heart transplantation:is clinical application now appropriate?[J].Journal of Immunology Research,2017,2017:2534653.
[3]PHELPS C J,KOIKE C,VAUGHT T D,et al.Production of alpha 1,3-galactosyltransferase-deficient pigs[J].Science,2003,299(5605):411-413.
[4]KLYMIUK N,AIGNER B,BREM G,et al.Genetic modification of pigs as organ donors for xenotransplantation[J].Molecular Reproduction&Development,2010,77(3):209-221.
[5]FISHMAN J A.Infectious disease risks in xenotransplantation[J].American Journal of Transplantation,2018,18(8):1857-1864.
[6]DENNER J,SCOBIE L,SCHUURMAN H J.Is it currently possible to evaluate the risk posed by PERVs for clinical xenotransplantation?[J].Xenotransplantation,2018,25(4):e12403.
[7]WEISS R A.Infection hazards of xenotransplantation:retrospect and prospect[J].Xenotransplantation,2018,25(4):e12401.
[8]PATIENCE C,TAKEUCHI Y,WEISS R A.Infection of human cells by an endogenous retrovirus of pigs[J].Nature Medicine,1997,3(3):282-286.
[9]LOPATA K,WOJDAS E,NOWAK R,et al.Porcine endogenous retrovirus(PERV)-molecular structure and replication strategy in the context of retroviral infection risk of human cells[J].Frontiers in Microbiology,2018,9:730.
[10]CHIANG C Y,PAN Y R,CHOU L F,et al.Functional epitopes on porcine endogenous retrovirus envelope protein interacting with neutralizing antibody combining sites[J].Virology,2007,361(2):364-371.
[11]CHOI J,KIM H M,YOON J K,et al.Identification of porcine endogenous retrovirus(PERV)packaging sequence and development of PERV packaging viral vector system[J].Journal of Microbiology,2015,53(5):348-353.
[12]LIU G,LI Z,PAN M,et al.Genetic prevalence of porcine endogenous retrovirus in Chinese experimental miniature pigs[J].Transplantation Proceedings,2011,43(7):2762-2769.
[13]DENNER J.How active are porcine endogenous retroviruses(PERVs)?[J].Viruses,2016,8:215.
[14]FUJIMURA T,MIYAGAWA S,TAKAHAGI Y,et al.Prevalence of porcine endogenous retroviruses in domestic,minature,and genetically modified pigs in Japan[J].Transplantation Proceedings,2008,40(2):594-595.
[15]SEMAAN M,ROTEM A,BARKAI U,et al.Screening pigs for xenotransplantation:prevalence and expression of porcine endogenous retroviruses in G觟ttingen minipigs[J].Xenotransplantation,2013,20(3):148-156.
[16]邢晓为,薛立群,莫朝辉,等.湖南大围子猪内源性逆转录病毒的研究[J].中南大学学报(医学版)(XING Xiao-wei,XUELi-qun,MO Zhao-hui,et al.Porcine endogenous retrovirus in Daweizi pigs in Hunan[J].Journal of Central South University(Medical Sciences)),2006,31(6):838-842.
[17]XING X W,HAWTHORNE W J,YI S,et al.Investigation of porcine endogenous retrovirus in the conservation population of Ningxiang pig[J].Transplantation Proceedings,2009,41(10):4389-4393.
[18]邢晓为,薛立群,黄生强,等.湖南沙子岭猪内源性逆转录病毒的研究[J].遗传(XING Xiao-wei,XUE Li-qun,HUANG Shengqiang,et al.Research of porcine endogenous retrovirus in Shaziling pigs[J].Hereditas),2006,28(7):799-804.
[19]GUO F,XING X,HAWTHORNE W J,et al.Characterization of PERV in a new conserved pig herd as potential donor animals for xenotransplantation in China[J].Virology Journal,2014,11:212.
[20]GOLA J,MAZUREK U.Detection of porcine endogenous retrovirus in xenotransplantation[J].Reproductive Biology,2014,14(1):68-73.
[21]SHAH C A,BONI J,BISSET L R,et al.Ultra-sensitive and specific detection of porcine endogenous retrovirus(PERV)using a sequence-capture real-time PCR approach[J].Journal of Virological Methods,2003,109(2):209-216.
[22]MOON H J,PARK S J,KIM H K,et al.Simultaneous detection and subtyping of porcine endogenous retroviruses proviral DNA using the dual priming oligonucleotide system[J].Journal of Veterinary Science,2010,11(3):269-271.
[23]YANG H,LI Z,JIANG Q,et al.Ultrasensitive detection and subtyping of porcine endogenous retrovirus provirus based on magnetic nanoparticles and chemiluminescence[J].Journal of Nanoscience and Nanotechnology,2015,15(8):5597-5604.
[24]YANG H,LIU M,ZHOU B,et al.Chemiluminescent detection for estimating relative copy numbers of porcine endogenous retrovirus proviruses from Chinese minipigs based on magnetic nanoparticles[J].Journal of Nanoscience and Nanotechnology,2016,16(6):6505-6510.
[25]LAAN L J W V D,LOCKEY C,GRIFFETH B C,et al.Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice[J].Nature,2000,407(6800):90-94.
[26]MARTIN U,WINKLER M E,ID M,et al.Productive infection of primary human endothelial cells by pig endogenous retrovirus(PERV)[J].Xenotransplantation,2010,7(2):138-142.
[27]SPECKE V,RUBANT S,DENNER J.Productive infection of human primary cells and cell lines with porcine endogenous retroviruses[J].Virology,2001,285(2):177-180.
[28]GüELL M,NIU D,KAN Y,et al.PERV inactivation is necessary to guarantee absence of pig-to-patient PERVs transmission in xenotransplantation[J].Xenotransplantation,2017,24(6):e12366.
[29]刘金凤,唐海波,马玲,等.巴马小型猪内源性反转录病毒感染对HEK293细胞周期调控相关基因mRNA表达的影响[J].中国兽医学报(LIU Jin-feng,TANG Hai-bo,MA Ling,et al.Effects of BM porcine endogenous retrovirus infection on the expression of cyclin-related genes in HEK293 cells[J].Chinese Journal of Veterinary Science),2018,38(3):433-441.
[30]DENNER J.Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals?[J].Retrovirology,2018,15:28.
[31]VALDESGONZALEZ R,DORANTES L M,BRACHOBLAN-CHET E,et al.No evidence of porcine endogenous retrovirus in patients with type 1 diabetes after long-term porcine islet xenotransplantation[J].Journal of Medical Virology,2010,82(2):331-334.
[32]MOROZOV V A,WYNYARD S,MATSUMOTO S,et al.No PERV transmission during a clinical trial of pig islet cell transplantation[J].Virus Research,2017,227:34-40.
[33]PITKIN Z,MULLON C.Evidence of absence of porcine endogenous retrovirus(PERV)infection in patients treated with a bioartificial liver support system[J].Artificial Organs,2015,23(9):829-833.
[34]MEIJE Y,TONJES R R,FISHMAN J A.Retroviral restriction factors and infectious risk in xenotransplantation[J].American Journal of Transplantation,2010,10(7):1511-1516.
[35]WANG Y,WANG X,YE L,et al.Morphine suppresses IFNsignaling pathway and enhances AIDS virus infection[J].PLoSOne,2012,7(2):e31167.
[36]LEE D,LEE J,PARK N,et al.Analysis of natural recombination in porcine endogenous retrovirus envelope genes[J].Journal of Microbiology and Biotechnology,2008,18(3):585-590.
[37]MOURAD N I,CROSSAN C,CRUIKSHANK V,et al.Characterization of porcine endogenous retrovirus expression in neonatal and adult pig pancreatic islets[J].Xenotransplantation,2017,24(4):e12311.
[38]CROSSAN C,MOURAD N I,SMITH K,et al.Assessment of porcine endogenous retrovirus transmission across an alginate barrier used for the encapsulation of porcine islets[J].Xenotransplantation,2018,25(6):e12409.
[39]叶征,邢晓为,童琼娟,等.异种移植微囊化新生猪胰岛细胞受体感染PERV潜在风险分析[J].中南大学学报(医学版)(YEZheng,XING Xiao-wei,TONG Qiong-juan,et al.Potential risk of porcine endogenous retrovirus cross species transmission in neonatal pig islets under xenotransplantation condition[J].Journal of Central South University(Medical Sciences)),2007,32(5):747-752.
[40]DIECKHOFF B,PETERSEN B,KUES W A,et al.Knockdown of porcine endogenous retrovirus(PERV)expression by PERV-specific shRNA in transgenic pigs[J].Xenotransplantation,2010,15(1):36-45.
[41]LI Z G,LIU G B,PAN M X,et al.Knockdown of porcine endogenous retroviruses by RNA interference in Chinese experimental miniature pig fibroblasts[J].Transplantation Proceedings,2013,45(2):748-755.
[42]DENNER J.Can antiretroviral drugs be used to treat porcine endogenous retrovirus(PERV)infection after xenotransplantation?[J].Viruses,2017,9(8):213.
[43]DEMANGE A,YAJJOU-HAMALIAN H,GALLAY K,et al.Porcine endogenous retrovirus-A/C:biochemical properties of its integrase and susceptibility to raltegravir[J].Journal of General Virology,2015,96(10):3124-3130.
[44]ARGAW T,COLON-MORAN W,WILSON C.Susceptibility of porcine endogenous retrovirus to anti-retroviral inhibitors[J].Xenotransplantation,2016,23(2):151-158.
[45]YANG L,GüELL M,NIU D,et al.Genome-wide inactivation of porcine endogenous retroviruses(PERVs)[J].Science,2015,350(6264):1101-1104.
[46]NIU D,WEI H J,LIN L,et al.Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9[J].Science,2017,357(6357):1303-1307.
[47]ROSS M J,COATES P T.Using CRISPR to inactivate endogenous retroviruses in pigs:an important step toward safe xenotransplantation?[J].Kidney International,2018,93(1):4-6.
[48]FU Y,FODEN J A,KHAYTER C,et al.High-frequency offtarget mutagenesis induced by CRISPR-Cas nucleases in human cells[J].Nature Biotechnology,2013,31(9):822-826.
[49]IYER V,BOROVIAK K,THOMAS M,et al.No unexpected CRISPR-Cas9 off-target activity revealed by trio sequencing of gene-edited mice[J].PLoS Genetics,2018,14(7):e1007503.
[2]MCGREGOR C G A,BYRNE G W.Porcine to human heart transplantation:is clinical application now appropriate?[J].Journal of Immunology Research,2017,2017:2534653.
[3]PHELPS C J,KOIKE C,VAUGHT T D,et al.Production of alpha 1,3-galactosyltransferase-deficient pigs[J].Science,2003,299(5605):411-413.
[4]KLYMIUK N,AIGNER B,BREM G,et al.Genetic modification of pigs as organ donors for xenotransplantation[J].Molecular Reproduction&Development,2010,77(3):209-221.
[5]FISHMAN J A.Infectious disease risks in xenotransplantation[J].American Journal of Transplantation,2018,18(8):1857-1864.
[6]DENNER J,SCOBIE L,SCHUURMAN H J.Is it currently possible to evaluate the risk posed by PERVs for clinical xenotransplantation?[J].Xenotransplantation,2018,25(4):e12403.
[7]WEISS R A.Infection hazards of xenotransplantation:retrospect and prospect[J].Xenotransplantation,2018,25(4):e12401.
[8]PATIENCE C,TAKEUCHI Y,WEISS R A.Infection of human cells by an endogenous retrovirus of pigs[J].Nature Medicine,1997,3(3):282-286.
[9]LOPATA K,WOJDAS E,NOWAK R,et al.Porcine endogenous retrovirus(PERV)-molecular structure and replication strategy in the context of retroviral infection risk of human cells[J].Frontiers in Microbiology,2018,9:730.
[10]CHIANG C Y,PAN Y R,CHOU L F,et al.Functional epitopes on porcine endogenous retrovirus envelope protein interacting with neutralizing antibody combining sites[J].Virology,2007,361(2):364-371.
[11]CHOI J,KIM H M,YOON J K,et al.Identification of porcine endogenous retrovirus(PERV)packaging sequence and development of PERV packaging viral vector system[J].Journal of Microbiology,2015,53(5):348-353.
[12]LIU G,LI Z,PAN M,et al.Genetic prevalence of porcine endogenous retrovirus in Chinese experimental miniature pigs[J].Transplantation Proceedings,2011,43(7):2762-2769.
[13]DENNER J.How active are porcine endogenous retroviruses(PERVs)?[J].Viruses,2016,8:215.
[14]FUJIMURA T,MIYAGAWA S,TAKAHAGI Y,et al.Prevalence of porcine endogenous retroviruses in domestic,minature,and genetically modified pigs in Japan[J].Transplantation Proceedings,2008,40(2):594-595.
[15]SEMAAN M,ROTEM A,BARKAI U,et al.Screening pigs for xenotransplantation:prevalence and expression of porcine endogenous retroviruses in G觟ttingen minipigs[J].Xenotransplantation,2013,20(3):148-156.
[16]邢晓为,薛立群,莫朝辉,等.湖南大围子猪内源性逆转录病毒的研究[J].中南大学学报(医学版)(XING Xiao-wei,XUELi-qun,MO Zhao-hui,et al.Porcine endogenous retrovirus in Daweizi pigs in Hunan[J].Journal of Central South University(Medical Sciences)),2006,31(6):838-842.
[17]XING X W,HAWTHORNE W J,YI S,et al.Investigation of porcine endogenous retrovirus in the conservation population of Ningxiang pig[J].Transplantation Proceedings,2009,41(10):4389-4393.
[18]邢晓为,薛立群,黄生强,等.湖南沙子岭猪内源性逆转录病毒的研究[J].遗传(XING Xiao-wei,XUE Li-qun,HUANG Shengqiang,et al.Research of porcine endogenous retrovirus in Shaziling pigs[J].Hereditas),2006,28(7):799-804.
[19]GUO F,XING X,HAWTHORNE W J,et al.Characterization of PERV in a new conserved pig herd as potential donor animals for xenotransplantation in China[J].Virology Journal,2014,11:212.
[20]GOLA J,MAZUREK U.Detection of porcine endogenous retrovirus in xenotransplantation[J].Reproductive Biology,2014,14(1):68-73.
[21]SHAH C A,BONI J,BISSET L R,et al.Ultra-sensitive and specific detection of porcine endogenous retrovirus(PERV)using a sequence-capture real-time PCR approach[J].Journal of Virological Methods,2003,109(2):209-216.
[22]MOON H J,PARK S J,KIM H K,et al.Simultaneous detection and subtyping of porcine endogenous retroviruses proviral DNA using the dual priming oligonucleotide system[J].Journal of Veterinary Science,2010,11(3):269-271.
[23]YANG H,LI Z,JIANG Q,et al.Ultrasensitive detection and subtyping of porcine endogenous retrovirus provirus based on magnetic nanoparticles and chemiluminescence[J].Journal of Nanoscience and Nanotechnology,2015,15(8):5597-5604.
[24]YANG H,LIU M,ZHOU B,et al.Chemiluminescent detection for estimating relative copy numbers of porcine endogenous retrovirus proviruses from Chinese minipigs based on magnetic nanoparticles[J].Journal of Nanoscience and Nanotechnology,2016,16(6):6505-6510.
[25]LAAN L J W V D,LOCKEY C,GRIFFETH B C,et al.Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice[J].Nature,2000,407(6800):90-94.
[26]MARTIN U,WINKLER M E,ID M,et al.Productive infection of primary human endothelial cells by pig endogenous retrovirus(PERV)[J].Xenotransplantation,2010,7(2):138-142.
[27]SPECKE V,RUBANT S,DENNER J.Productive infection of human primary cells and cell lines with porcine endogenous retroviruses[J].Virology,2001,285(2):177-180.
[28]GüELL M,NIU D,KAN Y,et al.PERV inactivation is necessary to guarantee absence of pig-to-patient PERVs transmission in xenotransplantation[J].Xenotransplantation,2017,24(6):e12366.
[29]刘金凤,唐海波,马玲,等.巴马小型猪内源性反转录病毒感染对HEK293细胞周期调控相关基因mRNA表达的影响[J].中国兽医学报(LIU Jin-feng,TANG Hai-bo,MA Ling,et al.Effects of BM porcine endogenous retrovirus infection on the expression of cyclin-related genes in HEK293 cells[J].Chinese Journal of Veterinary Science),2018,38(3):433-441.
[30]DENNER J.Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals?[J].Retrovirology,2018,15:28.
[31]VALDESGONZALEZ R,DORANTES L M,BRACHOBLAN-CHET E,et al.No evidence of porcine endogenous retrovirus in patients with type 1 diabetes after long-term porcine islet xenotransplantation[J].Journal of Medical Virology,2010,82(2):331-334.
[32]MOROZOV V A,WYNYARD S,MATSUMOTO S,et al.No PERV transmission during a clinical trial of pig islet cell transplantation[J].Virus Research,2017,227:34-40.
[33]PITKIN Z,MULLON C.Evidence of absence of porcine endogenous retrovirus(PERV)infection in patients treated with a bioartificial liver support system[J].Artificial Organs,2015,23(9):829-833.
[34]MEIJE Y,TONJES R R,FISHMAN J A.Retroviral restriction factors and infectious risk in xenotransplantation[J].American Journal of Transplantation,2010,10(7):1511-1516.
[35]WANG Y,WANG X,YE L,et al.Morphine suppresses IFNsignaling pathway and enhances AIDS virus infection[J].PLoSOne,2012,7(2):e31167.
[36]LEE D,LEE J,PARK N,et al.Analysis of natural recombination in porcine endogenous retrovirus envelope genes[J].Journal of Microbiology and Biotechnology,2008,18(3):585-590.
[37]MOURAD N I,CROSSAN C,CRUIKSHANK V,et al.Characterization of porcine endogenous retrovirus expression in neonatal and adult pig pancreatic islets[J].Xenotransplantation,2017,24(4):e12311.
[38]CROSSAN C,MOURAD N I,SMITH K,et al.Assessment of porcine endogenous retrovirus transmission across an alginate barrier used for the encapsulation of porcine islets[J].Xenotransplantation,2018,25(6):e12409.
[39]叶征,邢晓为,童琼娟,等.异种移植微囊化新生猪胰岛细胞受体感染PERV潜在风险分析[J].中南大学学报(医学版)(YEZheng,XING Xiao-wei,TONG Qiong-juan,et al.Potential risk of porcine endogenous retrovirus cross species transmission in neonatal pig islets under xenotransplantation condition[J].Journal of Central South University(Medical Sciences)),2007,32(5):747-752.
[40]DIECKHOFF B,PETERSEN B,KUES W A,et al.Knockdown of porcine endogenous retrovirus(PERV)expression by PERV-specific shRNA in transgenic pigs[J].Xenotransplantation,2010,15(1):36-45.
[41]LI Z G,LIU G B,PAN M X,et al.Knockdown of porcine endogenous retroviruses by RNA interference in Chinese experimental miniature pig fibroblasts[J].Transplantation Proceedings,2013,45(2):748-755.
[42]DENNER J.Can antiretroviral drugs be used to treat porcine endogenous retrovirus(PERV)infection after xenotransplantation?[J].Viruses,2017,9(8):213.
[43]DEMANGE A,YAJJOU-HAMALIAN H,GALLAY K,et al.Porcine endogenous retrovirus-A/C:biochemical properties of its integrase and susceptibility to raltegravir[J].Journal of General Virology,2015,96(10):3124-3130.
[44]ARGAW T,COLON-MORAN W,WILSON C.Susceptibility of porcine endogenous retrovirus to anti-retroviral inhibitors[J].Xenotransplantation,2016,23(2):151-158.
[45]YANG L,GüELL M,NIU D,et al.Genome-wide inactivation of porcine endogenous retroviruses(PERVs)[J].Science,2015,350(6264):1101-1104.
[46]NIU D,WEI H J,LIN L,et al.Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9[J].Science,2017,357(6357):1303-1307.
[47]ROSS M J,COATES P T.Using CRISPR to inactivate endogenous retroviruses in pigs:an important step toward safe xenotransplantation?[J].Kidney International,2018,93(1):4-6.
[48]FU Y,FODEN J A,KHAYTER C,et al.High-frequency offtarget mutagenesis induced by CRISPR-Cas nucleases in human cells[J].Nature Biotechnology,2013,31(9):822-826.
[49]IYER V,BOROVIAK K,THOMAS M,et al.No unexpected CRISPR-Cas9 off-target activity revealed by trio sequencing of gene-edited mice[J].PLoS Genetics,2018,14(7):e1007503.