HPV11型L2E7融合蛋白的原核表达及其免疫效果观察
|
摘要
根据各种流行病学资料,肛门生殖器疣(GW)是世界上一个不容忽视的公众健康问题,每年用于GW的诊断治疗费用给人们带来了不小的经济负担。传统的治疗方法存在一定的缺陷,而且复发率高,于是人们在寻找更有效的治疗或辅助治疗方法。
GW与人乳头瘤病毒(Human papillomavirus,HPV)6型和11型的密切关系10年前就已经明确。GW病灶会由一个逐渐扩增成多个,常常是旧的和新的疣体并存。可以解释为当上皮细胞局部受损伤的时候,上皮细胞的完整性遭到破坏,旧病灶脱落释放的HPV通过表皮的微小创伤进入组织,感染新的上皮基底层细胞。所以被HPV感染的细胞受感染的程度不一:处于非整合状态的部位,HPV的早晚期基因E6、E7、L1、E2都有表达;与宿主细胞DNA整合的仅能检测到E6、E7的表达;对于这种纷乱混杂的感染状态,就应该既要预防HPV的扩散感染,又要清除已被感染的细胞和相关病灶。
鉴于上述原因,人们一直在研制HPV疫苗,通过预防和治疗HPV感染的策略,达到预防和治疗GW的目的。预防性疫苗免疫策略主要集中在如何诱发出针对HPV相关表位的高滴度中和抗体来预防感染。以HPV衣壳蛋白L1,L2为靶抗原制备的病毒样颗粒(VLP)是预防性疫苗的主流,目前Merk公司的16、18、6、11型四价VLP疫苗已经上市。治疗性疫苗的关键是诱发针对病毒蛋白的细胞免疫,清除病灶和感染细胞,由于HPV-6,11型的两个早期蛋白E6,E7在疣体中持续表达,并且与疣复发密切相关,它们是治疗性疫苗理想的靶抗原。由英国和比利时分别研制的HPV6b L2E7融合蛋白疫苗都已经进行了Ⅱ期临床实验。
本研究在实验室已构建的HPV6bL2E7、HPV16L2E7治疗性疫苗基础上,构建HPV11L2E7融合蛋白原核表达系统,得到纯化的L2E7蛋白,并在小鼠体内评价其免疫原性。首先我们从尖锐湿疣组织经PCR扩增获得人乳头瘤病毒11型L2、E7编码区基因,其序列与发表的序列比对(序列号M14119),L2有两处突变,因未引起氨基酸的改变,为同义突变;E7有一处碱基由“G”变为“T”,相应位置的氨基酸由“A”变为“S”。构建pMD18T HPV11L2E7质粒,测序证实获得了L2E7融合基因。将融合的L2E7基因连接至缺失His的原核表达载体pETga,构建pET9a HPV11L2E7原核表达重组质粒。在大肠杆菌宿主菌BL21(DE3+)中经IPTG诱导高效表达了L2E7融合蛋白(553个氨基酸),经SDS-PAGE电泳和Western Blotting鉴定,表明成功表达了L2E7蛋白。诱导表达L2E7蛋白,收获、洗涤包涵体溶解于8M尿素(PH 8.3)进行CM离子交换介质纯化,纯化的蛋白通过Gel-Pro 3.1软件分析其纯度为83.8%。
纯化的L2E7蛋白与佐剂CpG-ODN和氢氧化铝免疫6～8周龄的BALB/c小鼠,进行细胞、体液免疫指标的检测。酶联免疫斑点实验(Enzyme linkedimmunospot,ELISPOT)显示,经该蛋白两次免疫后,小鼠脾单个核细胞(SMNC)体外HPV11E7肽库特异性IFN-γ分泌的斑点数为42.5±6.473/8×10~5脾细胞,与对照组(1.8±0.7528/8×10~5脾细胞)相比较,差别具有统计学意义(Q=16.3600,P<0.01)。细胞因子染色表明,实验组CD4/IFN-γ双阳性的细胞比例为1.8±0.1%,CD8/IFN-γ双阳性的细胞比例为0.3±0.1%,都高于对照组。酶联免疫吸附实验(ELISA)检测小鼠血清中L2和E7的特异性抗体,L2_(100-120)和E7的IgG都达到了1∶8000。
综上所述,原核表达纯化的HPV11L2E7融合蛋白不仅可以在小鼠体内引起HPV11E7特异性的细胞免疫反应,并且也能诱发针对HPV11L2和E7的特异性体液免疫反应,能作为尖锐湿疣免疫治疗候选疫苗。
Genital wart(GW)is a significant public health problem across the world according to the data of epidemiology.Annually the cost of GW's diagnosis and therapy is a great burdern to people.Due to the defects of traditionary therapies and the high recurrence of GW,people began to pursue the effective therapeutic or aid-therapeutic methods.
It was cleared that the close association between GW and Human papillomavirus (HPV)type 11 and 6 10 years ago.Once genital wart exists in one place then it usually spreads to other places and becomes polyinfection.HPV released from past lesions would infect the new basal cell layer when epithelial cells were injured and the integrity of epithelia was destroyed.Therefore the infections of cells' were at different levels such as the early gene E6,E7 and late gene L1,L2 were expressed in non-integrated cells howerver in integrated cells only E6,E7 protein were detected.So we need to treat the disordered infections by preventing the diffusion of HPV infection and clearing the infected cells and lesions.
Thus people study vaccines to prevent and treat HPV infection with HPV vaccine so that to prevent and treat GW.Prophylactic vaccination strategies have focused on eliciting high titers of neutralizing antibodies to epitopes displayed on papillomaviruses and preventing the primary infection by HPV.In this respect,the virus-like particles(VLPs)targeting the capsid protein L1,L2 of HPV become the main currency.The quadrivalent VLPs HPV-16/18/6/11 produced by Merk went on the market in 2006.As to therapeutic vaccine,it is the vital point to induce the cell-mediated immune response to viral protein,then to eliminate the lesion and infected cells.Two early proteins of HPV-6,-11 E6 and E7 are expressed at GW continuously and are required for the maintenance and recurrence of GW.They represent good targets for developing therapeutic vaccines.Two kinds of fusion proteins HPV6bL2E7 produced by Britain and Belgium respectively had been carried on phaseⅡclinical trials.
In our study,we constructed the Escherichia coli(E.coli)prokaryotic expression system pET9aHPV11L2E7 on the basis of two therapeutic vaccines HPV6bL2E7 and HPV16L2E7 constructed by us.Purified the fusion protein L2E7 and studied the immunnogenicity in mice.
At first,we amplified HPV11 L2,E7 coding region from condyloma acuminata tissues by PCR.Then compared the sequences with published sequences on genebank(serial numobr:M14119).We found that there were two mutations in L2 gene and which were same-sense mutations.In E7 gene there was one mutation: the G changed to T which caused the corresponding amino acids changed from A to S.Thereafter we constructed the plasmid pMD18T HPV11L2E7 then sequenced and which showed that we got the fusion gene L2E7.Subsequently we connected fusion gene L2E7 to His depletion plasmid pET9a,established the recombinant plazmid pET9aHPV11L2E7 and sequenced.Fusion protein L2E7(553 amino acids) was expressed in host strain BL21(DE3~+)by IPTG inducing and identified by using SDS-PAGE and Western Blotting which indicated we had expressed L2E7 succesfully.We expressed L2E7 protein in host strain BL21(DE3~+)and harvested the inclusion then washed it twice with 1M Urea.At last we lysised the inclusion in 8M Urea(PH8.3)and purified with CM column.The purity of L2E7 analysed with software Gel-Pro 3.1 was 83.8%.
Purified L2E7 mixed with adjuvant CpG-ODN and AL(OH)_3 inoculated to BALB/c mice and its cell-mediated and humoral immunnogenicity was assessed. IFN-γ,enzyme-linked immunospot(ELISPOT)showed after primed/boost the frequency of HPV11 E7 peptides pool specific IFN-γsecreting counts are 42.5±6.473/8×10~5 splenocyte mononuclearcytes(SMNC).Compared with the control group(1.8±0.7528/8×10~5SMNC)the difference between experiment group and control group were statistic significant.Cytokine staining manifested that CD4/IFN-γpositive cells(1.8±0.1%)and CD8/IFN-γ,positive cells(0.3±0.1%)were higher than those in control group.Enzyme-linked immunosorbent assay(ELISA)were used to evaluate the HPV11 L2 and E7-specific antibody in the serum of mice.The titers of anti-L2_(100-120),E7 IgG both reached 1:8000.
In summery the mice in vivo experiment indicated that the purified protein L2E7 could induce HPVllE7 specific cell-mediated immune responses and humoral immune responses.It can be used as a candidate of genital wart immune therapeutic vaccine.
GW与人乳头瘤病毒(Human papillomavirus,HPV)6型和11型的密切关系10年前就已经明确。GW病灶会由一个逐渐扩增成多个,常常是旧的和新的疣体并存。可以解释为当上皮细胞局部受损伤的时候,上皮细胞的完整性遭到破坏,旧病灶脱落释放的HPV通过表皮的微小创伤进入组织,感染新的上皮基底层细胞。所以被HPV感染的细胞受感染的程度不一:处于非整合状态的部位,HPV的早晚期基因E6、E7、L1、E2都有表达;与宿主细胞DNA整合的仅能检测到E6、E7的表达;对于这种纷乱混杂的感染状态,就应该既要预防HPV的扩散感染,又要清除已被感染的细胞和相关病灶。
鉴于上述原因,人们一直在研制HPV疫苗,通过预防和治疗HPV感染的策略,达到预防和治疗GW的目的。预防性疫苗免疫策略主要集中在如何诱发出针对HPV相关表位的高滴度中和抗体来预防感染。以HPV衣壳蛋白L1,L2为靶抗原制备的病毒样颗粒(VLP)是预防性疫苗的主流,目前Merk公司的16、18、6、11型四价VLP疫苗已经上市。治疗性疫苗的关键是诱发针对病毒蛋白的细胞免疫,清除病灶和感染细胞,由于HPV-6,11型的两个早期蛋白E6,E7在疣体中持续表达,并且与疣复发密切相关,它们是治疗性疫苗理想的靶抗原。由英国和比利时分别研制的HPV6b L2E7融合蛋白疫苗都已经进行了Ⅱ期临床实验。
本研究在实验室已构建的HPV6bL2E7、HPV16L2E7治疗性疫苗基础上,构建HPV11L2E7融合蛋白原核表达系统,得到纯化的L2E7蛋白,并在小鼠体内评价其免疫原性。首先我们从尖锐湿疣组织经PCR扩增获得人乳头瘤病毒11型L2、E7编码区基因,其序列与发表的序列比对(序列号M14119),L2有两处突变,因未引起氨基酸的改变,为同义突变;E7有一处碱基由“G”变为“T”,相应位置的氨基酸由“A”变为“S”。构建pMD18T HPV11L2E7质粒,测序证实获得了L2E7融合基因。将融合的L2E7基因连接至缺失His的原核表达载体pETga,构建pET9a HPV11L2E7原核表达重组质粒。在大肠杆菌宿主菌BL21(DE3+)中经IPTG诱导高效表达了L2E7融合蛋白(553个氨基酸),经SDS-PAGE电泳和Western Blotting鉴定,表明成功表达了L2E7蛋白。诱导表达L2E7蛋白,收获、洗涤包涵体溶解于8M尿素(PH 8.3)进行CM离子交换介质纯化,纯化的蛋白通过Gel-Pro 3.1软件分析其纯度为83.8%。
纯化的L2E7蛋白与佐剂CpG-ODN和氢氧化铝免疫6～8周龄的BALB/c小鼠,进行细胞、体液免疫指标的检测。酶联免疫斑点实验(Enzyme linkedimmunospot,ELISPOT)显示,经该蛋白两次免疫后,小鼠脾单个核细胞(SMNC)体外HPV11E7肽库特异性IFN-γ分泌的斑点数为42.5±6.473/8×10~5脾细胞,与对照组(1.8±0.7528/8×10~5脾细胞)相比较,差别具有统计学意义(Q=16.3600,P<0.01)。细胞因子染色表明,实验组CD4/IFN-γ双阳性的细胞比例为1.8±0.1%,CD8/IFN-γ双阳性的细胞比例为0.3±0.1%,都高于对照组。酶联免疫吸附实验(ELISA)检测小鼠血清中L2和E7的特异性抗体,L2_(100-120)和E7的IgG都达到了1∶8000。
综上所述,原核表达纯化的HPV11L2E7融合蛋白不仅可以在小鼠体内引起HPV11E7特异性的细胞免疫反应,并且也能诱发针对HPV11L2和E7的特异性体液免疫反应,能作为尖锐湿疣免疫治疗候选疫苗。
Genital wart(GW)is a significant public health problem across the world according to the data of epidemiology.Annually the cost of GW's diagnosis and therapy is a great burdern to people.Due to the defects of traditionary therapies and the high recurrence of GW,people began to pursue the effective therapeutic or aid-therapeutic methods.
It was cleared that the close association between GW and Human papillomavirus (HPV)type 11 and 6 10 years ago.Once genital wart exists in one place then it usually spreads to other places and becomes polyinfection.HPV released from past lesions would infect the new basal cell layer when epithelial cells were injured and the integrity of epithelia was destroyed.Therefore the infections of cells' were at different levels such as the early gene E6,E7 and late gene L1,L2 were expressed in non-integrated cells howerver in integrated cells only E6,E7 protein were detected.So we need to treat the disordered infections by preventing the diffusion of HPV infection and clearing the infected cells and lesions.
Thus people study vaccines to prevent and treat HPV infection with HPV vaccine so that to prevent and treat GW.Prophylactic vaccination strategies have focused on eliciting high titers of neutralizing antibodies to epitopes displayed on papillomaviruses and preventing the primary infection by HPV.In this respect,the virus-like particles(VLPs)targeting the capsid protein L1,L2 of HPV become the main currency.The quadrivalent VLPs HPV-16/18/6/11 produced by Merk went on the market in 2006.As to therapeutic vaccine,it is the vital point to induce the cell-mediated immune response to viral protein,then to eliminate the lesion and infected cells.Two early proteins of HPV-6,-11 E6 and E7 are expressed at GW continuously and are required for the maintenance and recurrence of GW.They represent good targets for developing therapeutic vaccines.Two kinds of fusion proteins HPV6bL2E7 produced by Britain and Belgium respectively had been carried on phaseⅡclinical trials.
In our study,we constructed the Escherichia coli(E.coli)prokaryotic expression system pET9aHPV11L2E7 on the basis of two therapeutic vaccines HPV6bL2E7 and HPV16L2E7 constructed by us.Purified the fusion protein L2E7 and studied the immunnogenicity in mice.
At first,we amplified HPV11 L2,E7 coding region from condyloma acuminata tissues by PCR.Then compared the sequences with published sequences on genebank(serial numobr:M14119).We found that there were two mutations in L2 gene and which were same-sense mutations.In E7 gene there was one mutation: the G changed to T which caused the corresponding amino acids changed from A to S.Thereafter we constructed the plasmid pMD18T HPV11L2E7 then sequenced and which showed that we got the fusion gene L2E7.Subsequently we connected fusion gene L2E7 to His depletion plasmid pET9a,established the recombinant plazmid pET9aHPV11L2E7 and sequenced.Fusion protein L2E7(553 amino acids) was expressed in host strain BL21(DE3~+)by IPTG inducing and identified by using SDS-PAGE and Western Blotting which indicated we had expressed L2E7 succesfully.We expressed L2E7 protein in host strain BL21(DE3~+)and harvested the inclusion then washed it twice with 1M Urea.At last we lysised the inclusion in 8M Urea(PH8.3)and purified with CM column.The purity of L2E7 analysed with software Gel-Pro 3.1 was 83.8%.
Purified L2E7 mixed with adjuvant CpG-ODN and AL(OH)_3 inoculated to BALB/c mice and its cell-mediated and humoral immunnogenicity was assessed. IFN-γ,enzyme-linked immunospot(ELISPOT)showed after primed/boost the frequency of HPV11 E7 peptides pool specific IFN-γsecreting counts are 42.5±6.473/8×10~5 splenocyte mononuclearcytes(SMNC).Compared with the control group(1.8±0.7528/8×10~5SMNC)the difference between experiment group and control group were statistic significant.Cytokine staining manifested that CD4/IFN-γpositive cells(1.8±0.1%)and CD8/IFN-γ,positive cells(0.3±0.1%)were higher than those in control group.Enzyme-linked immunosorbent assay(ELISA)were used to evaluate the HPV11 L2 and E7-specific antibody in the serum of mice.The titers of anti-L2_(100-120),E7 IgG both reached 1:8000.
In summery the mice in vivo experiment indicated that the purified protein L2E7 could induce HPVllE7 specific cell-mediated immune responses and humoral immune responses.It can be used as a candidate of genital wart immune therapeutic vaccine.
引文
1.C.J.N.Lacey et al.Phase IIa Safety and Immunogenicity of a Therapeutic Vaccine,TA-GW,in Persons with Genital Warts.The jounal of Infectious Diseases 1999;179:612-8.
2.MA Yi-sheng et al.Analysis of trends in the STD epidemic in Shenzhen from 1994 to 2003.Guangdong Journal of Health and Epidemic.Prevention.
3.Insinga RP,Dasbach EJ,Elbasha EH.Assessing the annual economic burden of preventing and treating anogenital human papillomavirusrelated disease in the US:analytic framework and review of the literature.Pharmacoeconomics 2005;23(11):1107-22.
4.Charles J.N.Lacey.Therapy for genital human papillomavirus-related disease.Journal of Clinical Virology 32S(2005)S82-S90.
5.Charles J.N.Lacey.Burdern and management of non-cancerous HPV-related conditions:HPV-6/11 disease.Vaccine 24S3(2006)S3/35-S3/41.
6.de Villiers EM,Fauquet C,Broker TR,Bernard HU,Zur HH.Classification of papillomaviruses.Virology 2004;324(1):17-27.
7.Vandepapeliere P,Barrasso R,Meijer CJ,et al.Randomised controlled trial of an adjuvanted human papillomavirus(HPV)type 6 L2E7 vaccine:infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination.J Infect Dis 2005;192(12):2099-107.
8.Ronco LV,Karpova AY,Vidal M,et al.Human papillomavirus 16 E6oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity.Genes Dev,1998,12:2061-2072.
9.Park JS,Kim EJ,Kwon HJ,et al.Inactivation of interferon regulatory factor-1tumor suppressor protein by HPV E7-mediated immune evasion mechanism in cervical carcinogenesis.J Biol Chem,2000,275:6764-6769.
10.Stern PL,Brown M,Stacey SN,et al.Natural HPV immunity and vaccination strategies.J Clin Virol,2000,19:57-66.
11.Jennifer Gunter.Genital and perianal warts:New treatment opportunities for human papillomavirus infection.Am J Obstet Gynecol 2003;189:S3-S11.
12. M. Samso, J.R. Daban, S. Hansen i GR. Jones et al. Evidence for Sodium Dodecyl Sulfate/Protein Complexes Adopting a Necklace Structure. Eur. J. Biochem. 232 (1995) 818 824.
13. Deborah J. Armstrong, Ann Roman/The anomalous electrophoresis behavior of the hunman papillmavirus type 16 E7 protein is due to the high content of acidic amino acid residues. Biochemical and biophysical research communications.
14. Tim Beibarth et al. A systematic approach for comprehensive T-cell epitope discovery using peptide libraries. Bioimformatics. Vol. 21 Suppl. 1 2005, pages i29 -i37.
15. Raja AJ-Attiyah, Fatema A. Shaban et al. Synthetic Peptides Identify Promiscuous Human Th1 Cell Epitopes of the Secreted Mycobacterial Antigen MPB70. INFECTION AND IMMUNITY, Apr. 2003, p. 1953-1960.
16. Margaret Stanley.HPV vaccines. Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 20, No. 2, pp. 279-293, 2006
17. Juliane M. FIRZLAFF. Detection of human papillomavirus capsid antigens in various squamous epithelial lesions using antibodies directed against the L1 and L2 open reading frames. Virology 164,467-477(1988).
18. Stephen T. Oh, Michelle S. Longworth C.Eklund et al. A two-site enzyme immunoassay for quantitation of human papillomavirus type 16 particles. Journal of Virological Methods 53(1995)11-23.
19. Stephen T. Oh, Michelle S. Longworth et al Roles of the E6 and E7 Proteins in the Life Cycle of Low-Risk Human papillomavirus Type 11. JOURNAL OF VIROLOGY, Mar. 2004, p. 2620-2626.
20. Roden RB, Yutzy WH, Fallon R, et al. Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. Virology, 2000,270(2): 254-257.
21. Kawana K, Kawana Y, Yoshikawa H, et al. Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. Vaccine, 2001, 19(11-12): 1496-1502.
22. KEI KAWANA, HIROYUKI YOSHIKAWA et al. Common Neutralization Epitope in Minor.Capsid Protein L2 of Human Papillomavirus Types 16 and 6.JOURNAL OF VIROLOGY,July 1999,p.6188-6190.
23.Kawana K,Yasugi T,Kanda T,et al.Safety and imlnunogenicity of a peptide containing the cross-neutralization epitope of HPV16 L2 administered nasally in healthy volunteers.Vaccine,2003,21(27-30):4256-4260.
24.van der Burg SH,Kwappenberg KM,O'Neill T,et al.Pre-clinical safety and efficacy of TA-CIN,a recombinant HPV16 L2E6E7 fusion protein vaccine,in homologous and heterologous prime-boost regimens.Vaccine,2001,19(27):36524660.
25.de Jong A,O'Neill T,Khan AY,et al.Enhancement of human papillomavirus(HPV)type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN,an HPV16 L2ETE6 fusion protein vaccine.Vaccine,2002,20(29-30):3456-3464.
26.de Villiers EM,Fauquet C,Broker TR,Bernard HU,Zur HH.Classification of papillomaviruses.Virology 2004;324(1):17-27.
27.Gerad CM,Baudson N,Kraemer K,et al.Therapeutic potential of protein and adjuvant vaccinations on tumor growth.Vaccine,2001,19:2583-89.
28.Stern BV,Boehm BO,Lehmann MT.Vaccination with tumor peptide in CpG adjuvant protects via IFN-γ-dependent CD4 cell immunity.J Immunol,2002,168:6099.
29.Klinman DM.Immunotherapeutic uses of CpG oligodeoxy- nucleotides.Nature Rev,2004,4:1-10.
30.Lefeber DJ,Benaissa TB.Th1-directing adjuvants increase the immunogenicity of oligosaccharide-protein conjugate vaccines related to streptococcus pneumoniae type 3.Infect Immun,2003,71(12):6915-20.
31.Maaike E.Ressing.Human CTL Epitopes Encoded by Human Papillomavirus Type 16 E6 and E7 Identified Through In Vivo and In Vitro Immunogenicity Studies of HLA-A*0201-Binding Peptides.The Journal of Immunology,1995,154:5934-5943.
32.HPV16/18 E7-pulsed dentritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities.Gynecologic Oncology 100(2006)469-478.Alessandro D.Santin et al.
33.Alessandro D.Santin et al.Induction of Human Papillomavirus- Specific CD4~+ and CD8~+Lymphocytes by E7-Pulsed Autologous Dendritic Cells in Patients with Human Papillornavirus Type 16- and 18-Positive Cervical Cancer.Jounal of Virology,July 1999,p.5402-5410.
34.Ligia A.Pinto et al.Cellular immune responses to HPV-18,-31,and -53 in healthy volunteers imlnunized with recombinant HPV-16 L1 virus-like particles.Virology 353(2006)451-462.
35.Cheng-Tao Lin et al.Maitenance of CD8 effector T cell by CD4helper T cell eradicates growing tumors and promotes long-term tumor immunity.Vaccine24(2006)6199-6207.
36.Tal Vider,Martin Weigert et al.T-cell epitope repertoire as predicted from human and viral genomes.Yoram Louzoun.Molecular Immunology 43(2006)559-569.
37.安云庆 编著《免疫学基础》,北京科学技术出版社1998年9月第一版。
1. Walboomers JM , Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189(1):12-9.
2. Bryan JT, Developing an HPV vaccine to prevent cervical cancer and genital ward,Vaccine(2007),doi:10.1016/j.vaccine.2007.01.013.
3. Milde-Langosch K. Association of human papillomavirus infection with carcinoma of the cervix uteri and its precursor lesions : theoretical and practical implications [J] Virchows Arch , 2000 ,437: 227- 233.
4. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002 cancer incidence. Mortality and prevalence worldwide. IARC CancerBase No. 5 version 2.0. Lyon: IARC Press; 2004.
5. Nubia Mu noz,Chapter 1:HPV in the etiology of human cancer, Vaccine 24S3 (2006) S3/1-S3/10.
6. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 90. Human Papillomaviruses. Lyon: IARC; 2005.
7. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papilloma- virus types in head and neck SCCs worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467-75.
8. Pfister H. Chapter 8: Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 2003;31:52-6.
9. Scott 1U, Karp CL, Nuovo GJ. Human papillomavirus 16 and 18 expression in conjunctival Intraepithelial neoplasia. Ophthalmology 2002; 109:542-7.
10. Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical cancer and 33,542 women without cervical cancer from 25 epidemiological studies. Int J Cancer 2006;119:1108-24.
11. Appleby P et al. Carcinoma of the cervix and tobacco smoking: Collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 2006;118:1481-95.
12. Cogliano V, Grosse Y, Baan R, Straif K, Secretan B, EI Ghissassi F. Carcinogenicity of combined oestrogen-progestagen contraceptives and menopausal treatment.Lancet Oncol 2005;6:552-3.
13.Smith JS,Herrero R,Bosetti C,Mu noz N,Bosch FX,Eluf-Neto J,et al.Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer.J Natl Cancer Inst 2002;94:1604-13.
14.Smith JS,Bosetti C,Mu~noz N,Herrero R,Bosch FX,Eluf-Neto J,et al.Chlamydia trachomatis and invasive cervical cancer:a pooled analysis of the IARC multicentric case-control study.Int J Cancer 2004;111:431-9.
15.Palefsky JM,Holly EA.Chapter 6:Immunosuppression and coinfection with HIV.J Natl Cancer Inst Monogr 2003;31:41-6.
16.Garcia-Closas R,Castellsagu'e X,Bosch X,Gonzalez CA.The role of diet and nutrition in cervical carcinogenesis:a review of recent evidence.Int J Cancer 2005;117:629-37.
17.Lei K,Skarsvag S et al.Association between the HLA FQB1*0301 gene and human papillomavirus infection in high grade cervical intraepithelial neoplasia.Int J Gynaecol Pathol,1999,18:206-210.
18.de Villiers EM,Fauquet C,Broker TR,Bernard HU,Zur HH.Classification of papillomaviruses.Virology 2004;324(1):17-27.
19.Lacey CJ.Therapy for genital human papillomavirus-related disease.J Clin Virol 2005;32(Suppl 1):S82-90.
20.Vandepapeliere P,Barrasso R,et al.Randomised controlled trial of an adjuvanted human papillomavirus(HPV)type 6 L2E7 vaccine:infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination.J Infect Dis 2005;192(12):2099-107.
21.Charles J.N.Lacey.Burden and management of non- cancerous HPV-related conditions:HPV-6/11 disease.Vaccine 24S3(2006)S3/35-S3/41.
22.Manhart LE,Koutsky LA.Do condoms prevent genital HPV infection,external genital warts,or cervical neoplasia? A eta-analysis.Sex Transm Dis 2002;29(11):725-35.
23.Munk C,Svare EI,Poll P,Bock JE,Kjaer SK.History of genital warts in 10,838 women 20 to 29 years of age from the general population.Risk factors and association with Papanicolaou smear : history. Sex Transm Dis 1997;24(10):567-72.
24. Monteiro EF, Lacey CJ, Merrick D. The interrelation of demographic and geospatial risk factors between four common sexually transmitted diseases. Sex Transm Infect 20Q5;81(1):41-6.
25. Holmberg SD, Buchbinder SP, et al. The spectrum of medical conditions and symptoms before acquired immunodeficiency syndrome in homosexual and bisexual men infected with the human immunodeficiency virus. Am J Epidemiol 1995;141(5):395-404.
26. Silverberg MJ, Ahdieh L, Munoz A, Anastos K, Burk RD, Cu-UvinS, et al. The impact of HIV infection and immunodeficiency on human papilloma- virus type 6 or 11 infection and on genital warts. Sex Transm Dis 2002;29(8):427-35.
27. Stina Syrjanen, Mirja Puranen. Human papollomavirus infections in children: the potential role of maternal transmission. Crit Rev Oral Med, 11(2): 259- 274 (2000).
28. Stanley MA. Virus-keratinocyte interactions in the infectious cycle. In: Stern PL, Stanley MA, eds. Human papillomaviruses and cervical cancer. Oxford: Oxford University Press, 1994:116-131.
29. Evander M, Frazer IH, Payne E, et al. Identification of the alpha(6) integrin as a candidate receptor for papillomaviruses. J Virol, 1997,71(3):2449-2456.
30. Liu JS, Kuo SR, Broker TR, et al. The functions of human papillomavirus type 11 E1, E2 and E2c proteins in cell-free DNA replication. J Biol Chem, 1995, 270(45):27283-27291.
31. Sedman J, Stenlund A. Co-operative interaction between the initiator E1 and the transcriptional activator E2 is required for replicator specific DNA replication of bovine papillomavirus in vivo and in vitro. EMBO J, 1995,14(24):6218-6228.
32. Sedman T, Sedman J, Stenlund A. Binding of the E1 and E2 protein to the origin of replication of bovine papillomavirus. J Virol, 1997, 71(4):2887-2896.
33. Crook T, Vousden KH. HPV oncoprotein function. In: Lacey C, ed. Papillomavirus reviews: current research on papillomaviruses. Leeds: Leeds University Press, 1996:55-60.
34. Stoler MH, Rhodes CR, Whitbeck A, et al. Human papillomavirus type 16 and 18 gene expression in cervical neoplasias. Hum Pathol, 1992,23:117-128.
35. Durst M, Glitz D, Schneider A, et al. Human papilloavirus typel6 (HPV16) gene expression and DNA replication in cervical neoplasia: analysis by in situ hybridization. Virology, 1992:189(1):132-140.
36. Phelps WC, Howley PM. Transcriptional Trans-activation by the human papillomavirus type 16 E2 gene product. J Virol, 1987,61:1630-1638.
37. Bernard BA, Bailly C, Lenoir MC, et al. The HPV 18 E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J Virol, 1989, 63: 4317-4324.
38. Demeret C, Desaintes C, Yaniv M, et al. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. J Virol, 1997,71:9343-9349.
39. DiMaio D, Lai CC, Mattoon D. The platelet-derived growth factor b receptor as a target of the bovine papillomavirus E5 protein. Cytokine Growth Factor Rev, 2000,11:283-293.
40 . Munger K, Howley PM. Human papillomavirus immortalization and transformation function. Virus Res, 2002, 89:213-228.
41. Leechanachai P, Banks L, Moreau F, et al. The E5 gene from human papillomavirus type 16 is an oncogene which enhances growth factor-mediated signal transduction to the nucleus. Oncogene, 1992,7:17-25.
42. Storey A, Greenfield I, Banks L, et al. Lack of immortalizing activity of a human papillomavirus type 16 variant DNA with a mutation in the E2 gene isolated from normal human cervical keratinocytes. Oncogene, 1992, 7:459-465.
43. Straight SW, Hinkle PM, Jewers RJ, et al. The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects down regulation of the epidermal growth factor receptor in keratinocytes. J Virol, 1993, 67:4521-4532.
44. Rodriguez MI, Finbow ME, Alonso A. Binding of human papillomavirus 16 E5 to the 16kDa subunit c(proteolipid) of the vacuolar H~+-ATPase can be dissociated from the E5-mediated epidermal growth factor receptor overactivation. Oncogene, 2000,19: 3727-3732.
45. Werness BA, Levine AJ, Howley PM. Association of human, papillomavirus types 16 and 18 E6 proteins with p53. Science, 1990,248: 76-79.
46. Hubbert NL, Sedman SA, Schiller JX Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. J Virol, 1992, 66: 6237-6241.
47. Scheffner M, Werness BA, Huibregtse JM, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promote the degradation of p53. Cell, 1990, 63:1129-1136.
48. Lechner MS, Mack DH, Finicle AB, et al. Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO, 1992,11: 3045-3052.
49. Jackson S, Harwood C, Thomas M, et al. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev, 2000, 14: 3065-3073.
50. Veldman T, Horikawa I, Barrett JC, et al. Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J Virol, 2001,75: 4467-4472.
51. Oda H, Kumar S, Howley PM. Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proc Natl Acad Sci USA, 1999, 96: 9557-9562.
52. Reinstein E, Scheffner M, Oren M, et al. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene, 2000,19: 5944-5950.
53. Cobrinik D, Dowdy SF, Hinds PW, et al. The retinoblastoma protein and the regulation of cell cycling. TIBS, 1992,17: 312-315.
54. Zerfass-Thome K, Zwerschke W, Mannhardt B, et al. Inactivation of the cdk inhibitor p27KIPl by the human papillomavirus type 16 E7 oncoprotein. Oncogene, 1996,13: 2323-2330.
55. Stephen T. Oh, Michelle S. Longworth et al. Roles of the E6 and E7 Proteins in the Life Cycle of Low-Risk Human papillomavirus Type 11. JOURNAL OF VIROLOGY, Mar. 2004, p. 2620-2626.
56. Thomas M, Banks L.Inhibition of BAK-induced apoptosis by HPV-18 E6.Oncogene, 1998,17: 2943-2954.
57. Winer RL, Kiviat NB et al. Development and duration of human papilloma-virus lesions, after initial infection. The Journal of Infectious Diseases. 2005;191(5):731-738.
58. Khan MJ, Castle PE et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical pratice. Journal of the National Cancer Institute. 2005;97(14): 1072-1079.
59. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L,Mariotto A, Feuer EJ, Edwards BK, editors. SEER Cancer Statistics Review, 1975-2002. Bethesda, MD: National Cancer Institute; 2005. http:// seer. cancer. gov/csr/1975 2002/.
60. Sant M, Aareleid T, Berrino F, Bielska LM, Carli PM, Faivre J, et al. EUROCARE-3: survival of cancer patients diagnosed 1990-94—results and commentary. Ann Oncol 2003; 14 (Suppl.5):v61-v118.
61. Gondos A, Chokunonga E, Brenner H, Parkin DM, Sankila R, Borok MZ, et al. Cancer survival in a southern African urban population. Int J Cancer 2004;112(5):860-4.
62. Insiga RP, Glass AG, Rush BB. The health care cost of cervical human papillomavirus-related disease. American Journal of Obstetrics and Gynecology. 2004;191(1):114-120.
63. Fazer IH. Immunology of papillomavirus infection. Curr Opin Immunol, 1996, 8:484-491.
64. Mao C,Hughes JP et al.Clinical findings among young women with genital human papillomavirus infection. American Journal of Obstetrics and Gynecology. 2003;188(3):677-684.
65. Sherman ME, Lorincz AT et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort abalysis. Jounal of the National Cancer Institute Monographs. 2003;(31):20-28.
66. Arany I, Tyring SK, Stanley MA, et al. Enhancement of the innate and cellular immune imiquimod cream 5%. Antiviral Res, 1999,43(1):55-63.
67. Nicholls PK, Moore PF, Anderson DM, et al. Regression of canine oral papillomas is associated with infiltration of CD4~+and CD8~+ lymphocytes. Virology, 2001,283(1): 31-39.
68. Stanley M, Coleman N, Chambers M. The host response, to lesions induced by human papillomavirus. Ciba Found Symp, 1994,187:21-44.
69. Nakagawa M,Stites DP, Farhat S, et al. Cytotoxic T lymphocyte responses to E6 and E7 proteins of human papillomavirus type 16: relationship to cervical intraepithelial neoplasia. J Infect Dis, 1997,175: 927-931.
70. Alexander M, Salgaller ML, Celis E, et al. Generation of tumor-specific cytolytic T lymphocytes from peripheral blood of cervical cancer patients by in vitro stimulation with a synthetic human papillomavirus type 16 E7 epitope. Am J Obstet Gynecol, 1996,175:1586-1593.
71. Evans EM, Man S, Evans AS, et al. Infiltration of cervical cancer tissue with human papillomavirus-specific cytotoxic T-lymphocytes. Cancer Res, 1997, 57: 2943-2950.
72. Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer, 2002,2: 59-65.
73. Kadish AS, Ho GY, Burk RD, et al. Lymphoproliferative responses to human papillomavirus (HPV) type 16 proteins E6 and E7: outcome of HPV infection and associated neoplasia. J Natl Cancer Inst, 1997, 89:1285-1293.
74. Smyth LJ, Van Poelgeerst MI, Davidson EJ, et al. Immunological responses in women with human papillomavirus type 16 (HPV16)-associated anogenital intraepithelial neoplasia induced by heterologous prime-boost HPV-16 oncogene vaccination. Clin Cancer Res, 2004,10: 2954-2961.
75. Davidson EJ, Boswell CM, Sehr P, et al. Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer Res, 2003, 63: 6032-6041.
76. Stern PL, Brown M, Stacey SN, et al. Natural HPV immunity and vaccination strategies. J Clin Virol, 2000,19:57-66.
77. Jennifer Gunter. Genital and perianal warts:New treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol 2003; 189: S3-S11.
78. Matthews K, Leong CM, Baxter L, et al. Depletion of Langerhans cells in human papillomavirus type 16-infected skin is associated with E6-mediated down regulation of E-cadherin. J Virol, 2003, 77:8378-8385.
79. Tay SK, Jenkins D, Maddox P, et al. Subpopulations of Langerhans cells in cervical neoplasia. Br J Obstet Gyaecol, 1987,94:10-15.
80. Ronco LV, Karpova AY, Vidal M, et al.. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev, 1998,12:2061-2072.
81. Park JS, Kim EJ, Kwon HJ, et al. Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7-mediated immune evasion mechanism in cervical carcinogenesis. J Biol Chem, 2000, 275:6764-6769.
82. Campo MS. Animal models of papillomavirus pathogenesis. Virus Res, 2002, 89:249-261.
83. Hopfl R, Heim K, Christensen N, et al. Spontaneous regression of CIN and delayed-type hypersensitivity to HPV-16 oncoprotein E7. Lancet, 2000, 356: 1985-1986.
84. Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst, 2001, 93:284-292.
85. Carter JJ, Koutsky LA, Hughes JP, et al. Comparison of human papillomavirus type 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis, 2000,181:1911-1919.
86. Jochmus-Kudielka I. Antibodies against the human papillomavirus type 16 early proteins in human sera: correlation of anti-E7 reactivity with cervical cancer. J Natl Cancer Inst, 1989, 81:1698-1704.
87. Davidson EJ, Kitchener HC, Stem PL. The use of vaccines in the prevention and treatment of cervical cancer. Clin Oncol, 2002,14:193-200.
88 . Schneider-Maunoury S, Groissant O, Orth G. Integration of human papillomavirus type 16 DNA sequences: a possible early event in the progression of genital tumors. J Virol, 1987, 61: 3295-3298.
89. Touze A, Coursaget P. In vitro gene transfer using human papillomavirus-like particles. Nucleic Acids Res, 1998,26:1317-1323.
90 . Marais D, Passmore J-A, Maclean J, et al. A recombinant human papillomavirus (HPV) type 16L1-vaccinia virus murine challenge model demonstrates cell-mediated immunity against HPV virus-like particles. J Gen Virol, 1999, 80: 2471-2475.
91. Rudolf MP, Nieland JD, Da Silva DM, et al. Induction of HPV16 capsid protein-specific human T cell responses by virus-like particles. Biol Chem, 1999, 380: 335-340.
92. Kaufmann AM, Stern PL, Rankin EM, et al. Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing modified human papillomavirus (HPV)-16 and HPV-18 E6 and E7 genes, in women with progressive cervical cancer. Clin Cancer Res, 2002,8(12): 3676-3685.
93. Adams M, Borysiewicz LK, Fiander A, et al. Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer. Vaccine, 2001,19(17-19): 2549-2556.
94. Borysiewicz LK, Fiander A, Niraako M, et al. A recombinant vaccinia virus encoding human papillomavirus type 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet, 1996,347(9014): 1523-1527.
95. Corona Gutierrez CM, Tinoco A, Navarro T, et al. Therapeutic vaccination with MVA E2 can eliminate precancerous lesions(CIN1,CIN2 andCIN3) associated with infection by oncogenic human papillomavirus. Hum Gene Ther, 2004, 15(5): 421-431.
96. Ling M, Wu T-C: Therapeutic human papillomavirus vaccines. In: Cervical Cancer: From Rtiology to Prevention. Rohan TE, Shah KV (Eds), Kluwer Academic Publishers, Boston, MA, USA, 2004, 345-376.
97. Bermudez-Humaran LG, Cortes-Perez NG, Le Loir Y, et al. An inducible surface presentation system improves cellular immunity against human papillomavirus type 16 E7 antigen in mice after nasal administration with recombinant lactococci. J Med Microbiol, 2004,53(5): 427-433.
98.Sewell DA,Douven D,Pan ZK,et al.Regression of HPV-positive tumors treated with a new Listeria monocytogenes vaccine.Arch Otolaryngol Head Neck Surg,2004,130(1):92-97.
99.Chen YF,Lin CW,Tsao YP,et al.Cytotoxic-T-lymphocyte human papillomavirus type 16 E5 peptide with CpG-oligodeoxynucleotide can eliminate tumor growth in C57BL/6 mice.J Virol,2004,78(3):1333-1343.
100.Ressing ME,van Driel WJ,Brandt RM,et al.Detection of T helper responses,but not of human papillomavirus-specific cytotoxic T lymphocyte responses,after peptide vaccination of patients with cervical carcinoma.J Immunother,2000,23(2):255-266.
101.van Driel WJ,Ressing ME,Kenter GG,et al.Vaccination with HPV16peptides of patients with advanced cervical carcinoma:Clinical evaluation of a phase Ⅰ-Ⅱ trial.Eur J Cancer,1999,35(6):946-952.
102.Muderspach L,Wilczynski S,Roman L,et al.A phase Ⅰ trial of a human papillomavirus(HPV)peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive.Clin Cancer Res,2000,6(9):3406-3416.
103.Fausch SC,Da Silva DM,Eiben GL,et al.HPV protein/peptide vaccines:From animal models to clinical trials.Front Biosci,2003,8:S81-S91.
104.Thompson HS,Davies ML,Holding FP,et al.Phase Ⅰ safety and antigenicity of TA-GW:A recombinant HPV6 L2E7 vaccine for the treatment of genital warts.Vaccine,1999,17(1):40-49.
105.Lacey CJ,Thompson HS,Monteiro EF,et al.Phase Ⅱa safety and immunogenicity of a therapeutic vaccine,TA-GW,in person with genital warts.J Infect Dis,1999,179(3):612-618.
106.de Jong A,O'Neill T,Khan AY,et al.Enhancement of human papillomavirus(HPV)type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-ClN,an HPV16 L2E7E6 fusion protein vaccine.Vaccine,2002,20(29-30):3456-3464.
107.Hallez S,Simon P,Maudoux F,et al.Phase Ⅰ/Ⅱ trial of immunogenicity of a human papillomavirus(HPV)type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical Intraepithelial neoplasia. Cancer Immunol Immunother, 2004,53(7): 642-650.
108. Nardelli-Haefliger D, Roden RB, Benyacoub J, et al. Human papillomavirus type 16 virus-like particles expressed in attenuated Salmonella typhimurium elicit mucosal and systemic neutralizing antibodies in mice. Infect Immun, 1997, 65(8): 3328-3336.
109. Balmelli C, Roden R, Potts A, et al. Nasal immunization of mice with human papillomavirus type 16 virus-like particles elicits neutralizing antibodies in mucosal secretion. J Virol, 1998, 72(10): 8220-8229.
110. Koutsky LA, Ault ICA, Wheeler CM, et al. A controlled trial of human papillomavirus type 16 vaccine. N Engl J Med, 2002,347:1645-1651.
111. Pinto LA, Edwards J, Castle PE, et al. Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles. J Infect Dis, 2003,188(2): 327-338.
112. Roden RB, Yutzy WH, Fallon R, et al. Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. Virology, 2000, 270(2): 254-257.
113. Kawana K, Kawana Y, Yoshikawa H, et al. Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. Vaccine, 2001, 19(11-12): 1496-1502.
114. Kawana K, Yasugi T, Kanda T, et al. Safety and immunogenicity of a peptide containing the cross-neutralization epitope of HPV16 L2 administered nasally in healthy volunteers. Vaccine, 2003, 21(27-30): 4256-4260.
115. van der Burg SH, Kwappenberg KM, O'Neill T, et al. Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. Vaccine, 2001, 19(27): 3652-3660.
116. Sheets EE, Urban RG, Crum CP, et al. Immunotherapy of human cervical high-grade cervical Intraepithelial neoplasia with microparticle-delivered human papillomavirus 16 E7 plasmid DNA. Am J Obstet Gynecol, 2003,188(4):916-926.
117. Garcia F, Petry KU, Muderspach L, et al. ZYClOla for treatment of high-grade cervical Intraepithelial neoplasia: A randomized controlled trial. Obstet Gynecol, 2004,103(2):317-326.
118. Figdor CG, de Vries IJ, Lesterhuis WJ, et al. Dendritic cell immunotherapy: Mapping the way. Nat Med, 2004,10(5): 475-480.
119. Santin AD, Bellone S, Gokden M, et al. Vaccination with HPV-18 E7-pulsed dendritic cells in a patient with metastatic cervical cancer. N Engl J Med, 2002, 346(22):1752-1753.
120. Adams M, de Jong A, Havabi H, et al. In vivo induction of HPV 16 specific CTL and T helper responses in patients with advanced cervical cancer using autologous dendritic cells pulsed with tumor lysate. International Papillomavirus Conference, Florianopolis, Brazil, 2001,19: Abs P-99.
121. Adams M, Navabi H, Jasani B, et al. Dendritic cell(DC) based therapy for cervical cancer: Use of DC pulsed with tumor lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly[l]: poly[C12U] (Ampligen). Vaccine, 2003, 21(7-8):787-790.
122. Tobery TW, Smith JF, Kuklin N, et al. Effect of vaccine delivery system on the induction of HPV16Ll-specific humoral and cell-mediated immune responses in immunized rhesus macaques. Vaccine, 2003,21:1539-1547.
123. James Colgrove. The Ethics and Politics of Compulsory HPV Vaccination. The New England Journal of Medicine. December 7,2006.
124. Chapter 5: Updating the natural history of HPV and anogenital cancer. Anna-Barbara Moscicki, Mark Schiffman et al. Vaccine 24S3 (2006) S3/42-S3/51
2.MA Yi-sheng et al.Analysis of trends in the STD epidemic in Shenzhen from 1994 to 2003.Guangdong Journal of Health and Epidemic.Prevention.
3.Insinga RP,Dasbach EJ,Elbasha EH.Assessing the annual economic burden of preventing and treating anogenital human papillomavirusrelated disease in the US:analytic framework and review of the literature.Pharmacoeconomics 2005;23(11):1107-22.
4.Charles J.N.Lacey.Therapy for genital human papillomavirus-related disease.Journal of Clinical Virology 32S(2005)S82-S90.
5.Charles J.N.Lacey.Burdern and management of non-cancerous HPV-related conditions:HPV-6/11 disease.Vaccine 24S3(2006)S3/35-S3/41.
6.de Villiers EM,Fauquet C,Broker TR,Bernard HU,Zur HH.Classification of papillomaviruses.Virology 2004;324(1):17-27.
7.Vandepapeliere P,Barrasso R,Meijer CJ,et al.Randomised controlled trial of an adjuvanted human papillomavirus(HPV)type 6 L2E7 vaccine:infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination.J Infect Dis 2005;192(12):2099-107.
8.Ronco LV,Karpova AY,Vidal M,et al.Human papillomavirus 16 E6oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity.Genes Dev,1998,12:2061-2072.
9.Park JS,Kim EJ,Kwon HJ,et al.Inactivation of interferon regulatory factor-1tumor suppressor protein by HPV E7-mediated immune evasion mechanism in cervical carcinogenesis.J Biol Chem,2000,275:6764-6769.
10.Stern PL,Brown M,Stacey SN,et al.Natural HPV immunity and vaccination strategies.J Clin Virol,2000,19:57-66.
11.Jennifer Gunter.Genital and perianal warts:New treatment opportunities for human papillomavirus infection.Am J Obstet Gynecol 2003;189:S3-S11.
12. M. Samso, J.R. Daban, S. Hansen i GR. Jones et al. Evidence for Sodium Dodecyl Sulfate/Protein Complexes Adopting a Necklace Structure. Eur. J. Biochem. 232 (1995) 818 824.
13. Deborah J. Armstrong, Ann Roman/The anomalous electrophoresis behavior of the hunman papillmavirus type 16 E7 protein is due to the high content of acidic amino acid residues. Biochemical and biophysical research communications.
14. Tim Beibarth et al. A systematic approach for comprehensive T-cell epitope discovery using peptide libraries. Bioimformatics. Vol. 21 Suppl. 1 2005, pages i29 -i37.
15. Raja AJ-Attiyah, Fatema A. Shaban et al. Synthetic Peptides Identify Promiscuous Human Th1 Cell Epitopes of the Secreted Mycobacterial Antigen MPB70. INFECTION AND IMMUNITY, Apr. 2003, p. 1953-1960.
16. Margaret Stanley.HPV vaccines. Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 20, No. 2, pp. 279-293, 2006
17. Juliane M. FIRZLAFF. Detection of human papillomavirus capsid antigens in various squamous epithelial lesions using antibodies directed against the L1 and L2 open reading frames. Virology 164,467-477(1988).
18. Stephen T. Oh, Michelle S. Longworth C.Eklund et al. A two-site enzyme immunoassay for quantitation of human papillomavirus type 16 particles. Journal of Virological Methods 53(1995)11-23.
19. Stephen T. Oh, Michelle S. Longworth et al Roles of the E6 and E7 Proteins in the Life Cycle of Low-Risk Human papillomavirus Type 11. JOURNAL OF VIROLOGY, Mar. 2004, p. 2620-2626.
20. Roden RB, Yutzy WH, Fallon R, et al. Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. Virology, 2000,270(2): 254-257.
21. Kawana K, Kawana Y, Yoshikawa H, et al. Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. Vaccine, 2001, 19(11-12): 1496-1502.
22. KEI KAWANA, HIROYUKI YOSHIKAWA et al. Common Neutralization Epitope in Minor.Capsid Protein L2 of Human Papillomavirus Types 16 and 6.JOURNAL OF VIROLOGY,July 1999,p.6188-6190.
23.Kawana K,Yasugi T,Kanda T,et al.Safety and imlnunogenicity of a peptide containing the cross-neutralization epitope of HPV16 L2 administered nasally in healthy volunteers.Vaccine,2003,21(27-30):4256-4260.
24.van der Burg SH,Kwappenberg KM,O'Neill T,et al.Pre-clinical safety and efficacy of TA-CIN,a recombinant HPV16 L2E6E7 fusion protein vaccine,in homologous and heterologous prime-boost regimens.Vaccine,2001,19(27):36524660.
25.de Jong A,O'Neill T,Khan AY,et al.Enhancement of human papillomavirus(HPV)type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN,an HPV16 L2ETE6 fusion protein vaccine.Vaccine,2002,20(29-30):3456-3464.
26.de Villiers EM,Fauquet C,Broker TR,Bernard HU,Zur HH.Classification of papillomaviruses.Virology 2004;324(1):17-27.
27.Gerad CM,Baudson N,Kraemer K,et al.Therapeutic potential of protein and adjuvant vaccinations on tumor growth.Vaccine,2001,19:2583-89.
28.Stern BV,Boehm BO,Lehmann MT.Vaccination with tumor peptide in CpG adjuvant protects via IFN-γ-dependent CD4 cell immunity.J Immunol,2002,168:6099.
29.Klinman DM.Immunotherapeutic uses of CpG oligodeoxy- nucleotides.Nature Rev,2004,4:1-10.
30.Lefeber DJ,Benaissa TB.Th1-directing adjuvants increase the immunogenicity of oligosaccharide-protein conjugate vaccines related to streptococcus pneumoniae type 3.Infect Immun,2003,71(12):6915-20.
31.Maaike E.Ressing.Human CTL Epitopes Encoded by Human Papillomavirus Type 16 E6 and E7 Identified Through In Vivo and In Vitro Immunogenicity Studies of HLA-A*0201-Binding Peptides.The Journal of Immunology,1995,154:5934-5943.
32.HPV16/18 E7-pulsed dentritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities.Gynecologic Oncology 100(2006)469-478.Alessandro D.Santin et al.
33.Alessandro D.Santin et al.Induction of Human Papillomavirus- Specific CD4~+ and CD8~+Lymphocytes by E7-Pulsed Autologous Dendritic Cells in Patients with Human Papillornavirus Type 16- and 18-Positive Cervical Cancer.Jounal of Virology,July 1999,p.5402-5410.
34.Ligia A.Pinto et al.Cellular immune responses to HPV-18,-31,and -53 in healthy volunteers imlnunized with recombinant HPV-16 L1 virus-like particles.Virology 353(2006)451-462.
35.Cheng-Tao Lin et al.Maitenance of CD8 effector T cell by CD4helper T cell eradicates growing tumors and promotes long-term tumor immunity.Vaccine24(2006)6199-6207.
36.Tal Vider,Martin Weigert et al.T-cell epitope repertoire as predicted from human and viral genomes.Yoram Louzoun.Molecular Immunology 43(2006)559-569.
37.安云庆 编著《免疫学基础》,北京科学技术出版社1998年9月第一版。
1. Walboomers JM , Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189(1):12-9.
2. Bryan JT, Developing an HPV vaccine to prevent cervical cancer and genital ward,Vaccine(2007),doi:10.1016/j.vaccine.2007.01.013.
3. Milde-Langosch K. Association of human papillomavirus infection with carcinoma of the cervix uteri and its precursor lesions : theoretical and practical implications [J] Virchows Arch , 2000 ,437: 227- 233.
4. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002 cancer incidence. Mortality and prevalence worldwide. IARC CancerBase No. 5 version 2.0. Lyon: IARC Press; 2004.
5. Nubia Mu noz,Chapter 1:HPV in the etiology of human cancer, Vaccine 24S3 (2006) S3/1-S3/10.
6. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 90. Human Papillomaviruses. Lyon: IARC; 2005.
7. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papilloma- virus types in head and neck SCCs worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467-75.
8. Pfister H. Chapter 8: Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 2003;31:52-6.
9. Scott 1U, Karp CL, Nuovo GJ. Human papillomavirus 16 and 18 expression in conjunctival Intraepithelial neoplasia. Ophthalmology 2002; 109:542-7.
10. Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical cancer and 33,542 women without cervical cancer from 25 epidemiological studies. Int J Cancer 2006;119:1108-24.
11. Appleby P et al. Carcinoma of the cervix and tobacco smoking: Collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 2006;118:1481-95.
12. Cogliano V, Grosse Y, Baan R, Straif K, Secretan B, EI Ghissassi F. Carcinogenicity of combined oestrogen-progestagen contraceptives and menopausal treatment.Lancet Oncol 2005;6:552-3.
13.Smith JS,Herrero R,Bosetti C,Mu noz N,Bosch FX,Eluf-Neto J,et al.Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer.J Natl Cancer Inst 2002;94:1604-13.
14.Smith JS,Bosetti C,Mu~noz N,Herrero R,Bosch FX,Eluf-Neto J,et al.Chlamydia trachomatis and invasive cervical cancer:a pooled analysis of the IARC multicentric case-control study.Int J Cancer 2004;111:431-9.
15.Palefsky JM,Holly EA.Chapter 6:Immunosuppression and coinfection with HIV.J Natl Cancer Inst Monogr 2003;31:41-6.
16.Garcia-Closas R,Castellsagu'e X,Bosch X,Gonzalez CA.The role of diet and nutrition in cervical carcinogenesis:a review of recent evidence.Int J Cancer 2005;117:629-37.
17.Lei K,Skarsvag S et al.Association between the HLA FQB1*0301 gene and human papillomavirus infection in high grade cervical intraepithelial neoplasia.Int J Gynaecol Pathol,1999,18:206-210.
18.de Villiers EM,Fauquet C,Broker TR,Bernard HU,Zur HH.Classification of papillomaviruses.Virology 2004;324(1):17-27.
19.Lacey CJ.Therapy for genital human papillomavirus-related disease.J Clin Virol 2005;32(Suppl 1):S82-90.
20.Vandepapeliere P,Barrasso R,et al.Randomised controlled trial of an adjuvanted human papillomavirus(HPV)type 6 L2E7 vaccine:infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination.J Infect Dis 2005;192(12):2099-107.
21.Charles J.N.Lacey.Burden and management of non- cancerous HPV-related conditions:HPV-6/11 disease.Vaccine 24S3(2006)S3/35-S3/41.
22.Manhart LE,Koutsky LA.Do condoms prevent genital HPV infection,external genital warts,or cervical neoplasia? A eta-analysis.Sex Transm Dis 2002;29(11):725-35.
23.Munk C,Svare EI,Poll P,Bock JE,Kjaer SK.History of genital warts in 10,838 women 20 to 29 years of age from the general population.Risk factors and association with Papanicolaou smear : history. Sex Transm Dis 1997;24(10):567-72.
24. Monteiro EF, Lacey CJ, Merrick D. The interrelation of demographic and geospatial risk factors between four common sexually transmitted diseases. Sex Transm Infect 20Q5;81(1):41-6.
25. Holmberg SD, Buchbinder SP, et al. The spectrum of medical conditions and symptoms before acquired immunodeficiency syndrome in homosexual and bisexual men infected with the human immunodeficiency virus. Am J Epidemiol 1995;141(5):395-404.
26. Silverberg MJ, Ahdieh L, Munoz A, Anastos K, Burk RD, Cu-UvinS, et al. The impact of HIV infection and immunodeficiency on human papilloma- virus type 6 or 11 infection and on genital warts. Sex Transm Dis 2002;29(8):427-35.
27. Stina Syrjanen, Mirja Puranen. Human papollomavirus infections in children: the potential role of maternal transmission. Crit Rev Oral Med, 11(2): 259- 274 (2000).
28. Stanley MA. Virus-keratinocyte interactions in the infectious cycle. In: Stern PL, Stanley MA, eds. Human papillomaviruses and cervical cancer. Oxford: Oxford University Press, 1994:116-131.
29. Evander M, Frazer IH, Payne E, et al. Identification of the alpha(6) integrin as a candidate receptor for papillomaviruses. J Virol, 1997,71(3):2449-2456.
30. Liu JS, Kuo SR, Broker TR, et al. The functions of human papillomavirus type 11 E1, E2 and E2c proteins in cell-free DNA replication. J Biol Chem, 1995, 270(45):27283-27291.
31. Sedman J, Stenlund A. Co-operative interaction between the initiator E1 and the transcriptional activator E2 is required for replicator specific DNA replication of bovine papillomavirus in vivo and in vitro. EMBO J, 1995,14(24):6218-6228.
32. Sedman T, Sedman J, Stenlund A. Binding of the E1 and E2 protein to the origin of replication of bovine papillomavirus. J Virol, 1997, 71(4):2887-2896.
33. Crook T, Vousden KH. HPV oncoprotein function. In: Lacey C, ed. Papillomavirus reviews: current research on papillomaviruses. Leeds: Leeds University Press, 1996:55-60.
34. Stoler MH, Rhodes CR, Whitbeck A, et al. Human papillomavirus type 16 and 18 gene expression in cervical neoplasias. Hum Pathol, 1992,23:117-128.
35. Durst M, Glitz D, Schneider A, et al. Human papilloavirus typel6 (HPV16) gene expression and DNA replication in cervical neoplasia: analysis by in situ hybridization. Virology, 1992:189(1):132-140.
36. Phelps WC, Howley PM. Transcriptional Trans-activation by the human papillomavirus type 16 E2 gene product. J Virol, 1987,61:1630-1638.
37. Bernard BA, Bailly C, Lenoir MC, et al. The HPV 18 E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J Virol, 1989, 63: 4317-4324.
38. Demeret C, Desaintes C, Yaniv M, et al. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. J Virol, 1997,71:9343-9349.
39. DiMaio D, Lai CC, Mattoon D. The platelet-derived growth factor b receptor as a target of the bovine papillomavirus E5 protein. Cytokine Growth Factor Rev, 2000,11:283-293.
40 . Munger K, Howley PM. Human papillomavirus immortalization and transformation function. Virus Res, 2002, 89:213-228.
41. Leechanachai P, Banks L, Moreau F, et al. The E5 gene from human papillomavirus type 16 is an oncogene which enhances growth factor-mediated signal transduction to the nucleus. Oncogene, 1992,7:17-25.
42. Storey A, Greenfield I, Banks L, et al. Lack of immortalizing activity of a human papillomavirus type 16 variant DNA with a mutation in the E2 gene isolated from normal human cervical keratinocytes. Oncogene, 1992, 7:459-465.
43. Straight SW, Hinkle PM, Jewers RJ, et al. The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects down regulation of the epidermal growth factor receptor in keratinocytes. J Virol, 1993, 67:4521-4532.
44. Rodriguez MI, Finbow ME, Alonso A. Binding of human papillomavirus 16 E5 to the 16kDa subunit c(proteolipid) of the vacuolar H~+-ATPase can be dissociated from the E5-mediated epidermal growth factor receptor overactivation. Oncogene, 2000,19: 3727-3732.
45. Werness BA, Levine AJ, Howley PM. Association of human, papillomavirus types 16 and 18 E6 proteins with p53. Science, 1990,248: 76-79.
46. Hubbert NL, Sedman SA, Schiller JX Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. J Virol, 1992, 66: 6237-6241.
47. Scheffner M, Werness BA, Huibregtse JM, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promote the degradation of p53. Cell, 1990, 63:1129-1136.
48. Lechner MS, Mack DH, Finicle AB, et al. Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO, 1992,11: 3045-3052.
49. Jackson S, Harwood C, Thomas M, et al. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev, 2000, 14: 3065-3073.
50. Veldman T, Horikawa I, Barrett JC, et al. Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J Virol, 2001,75: 4467-4472.
51. Oda H, Kumar S, Howley PM. Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proc Natl Acad Sci USA, 1999, 96: 9557-9562.
52. Reinstein E, Scheffner M, Oren M, et al. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene, 2000,19: 5944-5950.
53. Cobrinik D, Dowdy SF, Hinds PW, et al. The retinoblastoma protein and the regulation of cell cycling. TIBS, 1992,17: 312-315.
54. Zerfass-Thome K, Zwerschke W, Mannhardt B, et al. Inactivation of the cdk inhibitor p27KIPl by the human papillomavirus type 16 E7 oncoprotein. Oncogene, 1996,13: 2323-2330.
55. Stephen T. Oh, Michelle S. Longworth et al. Roles of the E6 and E7 Proteins in the Life Cycle of Low-Risk Human papillomavirus Type 11. JOURNAL OF VIROLOGY, Mar. 2004, p. 2620-2626.
56. Thomas M, Banks L.Inhibition of BAK-induced apoptosis by HPV-18 E6.Oncogene, 1998,17: 2943-2954.
57. Winer RL, Kiviat NB et al. Development and duration of human papilloma-virus lesions, after initial infection. The Journal of Infectious Diseases. 2005;191(5):731-738.
58. Khan MJ, Castle PE et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical pratice. Journal of the National Cancer Institute. 2005;97(14): 1072-1079.
59. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L,Mariotto A, Feuer EJ, Edwards BK, editors. SEER Cancer Statistics Review, 1975-2002. Bethesda, MD: National Cancer Institute; 2005. http:// seer. cancer. gov/csr/1975 2002/.
60. Sant M, Aareleid T, Berrino F, Bielska LM, Carli PM, Faivre J, et al. EUROCARE-3: survival of cancer patients diagnosed 1990-94—results and commentary. Ann Oncol 2003; 14 (Suppl.5):v61-v118.
61. Gondos A, Chokunonga E, Brenner H, Parkin DM, Sankila R, Borok MZ, et al. Cancer survival in a southern African urban population. Int J Cancer 2004;112(5):860-4.
62. Insiga RP, Glass AG, Rush BB. The health care cost of cervical human papillomavirus-related disease. American Journal of Obstetrics and Gynecology. 2004;191(1):114-120.
63. Fazer IH. Immunology of papillomavirus infection. Curr Opin Immunol, 1996, 8:484-491.
64. Mao C,Hughes JP et al.Clinical findings among young women with genital human papillomavirus infection. American Journal of Obstetrics and Gynecology. 2003;188(3):677-684.
65. Sherman ME, Lorincz AT et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort abalysis. Jounal of the National Cancer Institute Monographs. 2003;(31):20-28.
66. Arany I, Tyring SK, Stanley MA, et al. Enhancement of the innate and cellular immune imiquimod cream 5%. Antiviral Res, 1999,43(1):55-63.
67. Nicholls PK, Moore PF, Anderson DM, et al. Regression of canine oral papillomas is associated with infiltration of CD4~+and CD8~+ lymphocytes. Virology, 2001,283(1): 31-39.
68. Stanley M, Coleman N, Chambers M. The host response, to lesions induced by human papillomavirus. Ciba Found Symp, 1994,187:21-44.
69. Nakagawa M,Stites DP, Farhat S, et al. Cytotoxic T lymphocyte responses to E6 and E7 proteins of human papillomavirus type 16: relationship to cervical intraepithelial neoplasia. J Infect Dis, 1997,175: 927-931.
70. Alexander M, Salgaller ML, Celis E, et al. Generation of tumor-specific cytolytic T lymphocytes from peripheral blood of cervical cancer patients by in vitro stimulation with a synthetic human papillomavirus type 16 E7 epitope. Am J Obstet Gynecol, 1996,175:1586-1593.
71. Evans EM, Man S, Evans AS, et al. Infiltration of cervical cancer tissue with human papillomavirus-specific cytotoxic T-lymphocytes. Cancer Res, 1997, 57: 2943-2950.
72. Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer, 2002,2: 59-65.
73. Kadish AS, Ho GY, Burk RD, et al. Lymphoproliferative responses to human papillomavirus (HPV) type 16 proteins E6 and E7: outcome of HPV infection and associated neoplasia. J Natl Cancer Inst, 1997, 89:1285-1293.
74. Smyth LJ, Van Poelgeerst MI, Davidson EJ, et al. Immunological responses in women with human papillomavirus type 16 (HPV16)-associated anogenital intraepithelial neoplasia induced by heterologous prime-boost HPV-16 oncogene vaccination. Clin Cancer Res, 2004,10: 2954-2961.
75. Davidson EJ, Boswell CM, Sehr P, et al. Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer Res, 2003, 63: 6032-6041.
76. Stern PL, Brown M, Stacey SN, et al. Natural HPV immunity and vaccination strategies. J Clin Virol, 2000,19:57-66.
77. Jennifer Gunter. Genital and perianal warts:New treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol 2003; 189: S3-S11.
78. Matthews K, Leong CM, Baxter L, et al. Depletion of Langerhans cells in human papillomavirus type 16-infected skin is associated with E6-mediated down regulation of E-cadherin. J Virol, 2003, 77:8378-8385.
79. Tay SK, Jenkins D, Maddox P, et al. Subpopulations of Langerhans cells in cervical neoplasia. Br J Obstet Gyaecol, 1987,94:10-15.
80. Ronco LV, Karpova AY, Vidal M, et al.. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev, 1998,12:2061-2072.
81. Park JS, Kim EJ, Kwon HJ, et al. Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7-mediated immune evasion mechanism in cervical carcinogenesis. J Biol Chem, 2000, 275:6764-6769.
82. Campo MS. Animal models of papillomavirus pathogenesis. Virus Res, 2002, 89:249-261.
83. Hopfl R, Heim K, Christensen N, et al. Spontaneous regression of CIN and delayed-type hypersensitivity to HPV-16 oncoprotein E7. Lancet, 2000, 356: 1985-1986.
84. Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst, 2001, 93:284-292.
85. Carter JJ, Koutsky LA, Hughes JP, et al. Comparison of human papillomavirus type 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis, 2000,181:1911-1919.
86. Jochmus-Kudielka I. Antibodies against the human papillomavirus type 16 early proteins in human sera: correlation of anti-E7 reactivity with cervical cancer. J Natl Cancer Inst, 1989, 81:1698-1704.
87. Davidson EJ, Kitchener HC, Stem PL. The use of vaccines in the prevention and treatment of cervical cancer. Clin Oncol, 2002,14:193-200.
88 . Schneider-Maunoury S, Groissant O, Orth G. Integration of human papillomavirus type 16 DNA sequences: a possible early event in the progression of genital tumors. J Virol, 1987, 61: 3295-3298.
89. Touze A, Coursaget P. In vitro gene transfer using human papillomavirus-like particles. Nucleic Acids Res, 1998,26:1317-1323.
90 . Marais D, Passmore J-A, Maclean J, et al. A recombinant human papillomavirus (HPV) type 16L1-vaccinia virus murine challenge model demonstrates cell-mediated immunity against HPV virus-like particles. J Gen Virol, 1999, 80: 2471-2475.
91. Rudolf MP, Nieland JD, Da Silva DM, et al. Induction of HPV16 capsid protein-specific human T cell responses by virus-like particles. Biol Chem, 1999, 380: 335-340.
92. Kaufmann AM, Stern PL, Rankin EM, et al. Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing modified human papillomavirus (HPV)-16 and HPV-18 E6 and E7 genes, in women with progressive cervical cancer. Clin Cancer Res, 2002,8(12): 3676-3685.
93. Adams M, Borysiewicz LK, Fiander A, et al. Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer. Vaccine, 2001,19(17-19): 2549-2556.
94. Borysiewicz LK, Fiander A, Niraako M, et al. A recombinant vaccinia virus encoding human papillomavirus type 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet, 1996,347(9014): 1523-1527.
95. Corona Gutierrez CM, Tinoco A, Navarro T, et al. Therapeutic vaccination with MVA E2 can eliminate precancerous lesions(CIN1,CIN2 andCIN3) associated with infection by oncogenic human papillomavirus. Hum Gene Ther, 2004, 15(5): 421-431.
96. Ling M, Wu T-C: Therapeutic human papillomavirus vaccines. In: Cervical Cancer: From Rtiology to Prevention. Rohan TE, Shah KV (Eds), Kluwer Academic Publishers, Boston, MA, USA, 2004, 345-376.
97. Bermudez-Humaran LG, Cortes-Perez NG, Le Loir Y, et al. An inducible surface presentation system improves cellular immunity against human papillomavirus type 16 E7 antigen in mice after nasal administration with recombinant lactococci. J Med Microbiol, 2004,53(5): 427-433.
98.Sewell DA,Douven D,Pan ZK,et al.Regression of HPV-positive tumors treated with a new Listeria monocytogenes vaccine.Arch Otolaryngol Head Neck Surg,2004,130(1):92-97.
99.Chen YF,Lin CW,Tsao YP,et al.Cytotoxic-T-lymphocyte human papillomavirus type 16 E5 peptide with CpG-oligodeoxynucleotide can eliminate tumor growth in C57BL/6 mice.J Virol,2004,78(3):1333-1343.
100.Ressing ME,van Driel WJ,Brandt RM,et al.Detection of T helper responses,but not of human papillomavirus-specific cytotoxic T lymphocyte responses,after peptide vaccination of patients with cervical carcinoma.J Immunother,2000,23(2):255-266.
101.van Driel WJ,Ressing ME,Kenter GG,et al.Vaccination with HPV16peptides of patients with advanced cervical carcinoma:Clinical evaluation of a phase Ⅰ-Ⅱ trial.Eur J Cancer,1999,35(6):946-952.
102.Muderspach L,Wilczynski S,Roman L,et al.A phase Ⅰ trial of a human papillomavirus(HPV)peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive.Clin Cancer Res,2000,6(9):3406-3416.
103.Fausch SC,Da Silva DM,Eiben GL,et al.HPV protein/peptide vaccines:From animal models to clinical trials.Front Biosci,2003,8:S81-S91.
104.Thompson HS,Davies ML,Holding FP,et al.Phase Ⅰ safety and antigenicity of TA-GW:A recombinant HPV6 L2E7 vaccine for the treatment of genital warts.Vaccine,1999,17(1):40-49.
105.Lacey CJ,Thompson HS,Monteiro EF,et al.Phase Ⅱa safety and immunogenicity of a therapeutic vaccine,TA-GW,in person with genital warts.J Infect Dis,1999,179(3):612-618.
106.de Jong A,O'Neill T,Khan AY,et al.Enhancement of human papillomavirus(HPV)type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-ClN,an HPV16 L2E7E6 fusion protein vaccine.Vaccine,2002,20(29-30):3456-3464.
107.Hallez S,Simon P,Maudoux F,et al.Phase Ⅰ/Ⅱ trial of immunogenicity of a human papillomavirus(HPV)type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical Intraepithelial neoplasia. Cancer Immunol Immunother, 2004,53(7): 642-650.
108. Nardelli-Haefliger D, Roden RB, Benyacoub J, et al. Human papillomavirus type 16 virus-like particles expressed in attenuated Salmonella typhimurium elicit mucosal and systemic neutralizing antibodies in mice. Infect Immun, 1997, 65(8): 3328-3336.
109. Balmelli C, Roden R, Potts A, et al. Nasal immunization of mice with human papillomavirus type 16 virus-like particles elicits neutralizing antibodies in mucosal secretion. J Virol, 1998, 72(10): 8220-8229.
110. Koutsky LA, Ault ICA, Wheeler CM, et al. A controlled trial of human papillomavirus type 16 vaccine. N Engl J Med, 2002,347:1645-1651.
111. Pinto LA, Edwards J, Castle PE, et al. Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles. J Infect Dis, 2003,188(2): 327-338.
112. Roden RB, Yutzy WH, Fallon R, et al. Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. Virology, 2000, 270(2): 254-257.
113. Kawana K, Kawana Y, Yoshikawa H, et al. Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. Vaccine, 2001, 19(11-12): 1496-1502.
114. Kawana K, Yasugi T, Kanda T, et al. Safety and immunogenicity of a peptide containing the cross-neutralization epitope of HPV16 L2 administered nasally in healthy volunteers. Vaccine, 2003, 21(27-30): 4256-4260.
115. van der Burg SH, Kwappenberg KM, O'Neill T, et al. Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. Vaccine, 2001, 19(27): 3652-3660.
116. Sheets EE, Urban RG, Crum CP, et al. Immunotherapy of human cervical high-grade cervical Intraepithelial neoplasia with microparticle-delivered human papillomavirus 16 E7 plasmid DNA. Am J Obstet Gynecol, 2003,188(4):916-926.
117. Garcia F, Petry KU, Muderspach L, et al. ZYClOla for treatment of high-grade cervical Intraepithelial neoplasia: A randomized controlled trial. Obstet Gynecol, 2004,103(2):317-326.
118. Figdor CG, de Vries IJ, Lesterhuis WJ, et al. Dendritic cell immunotherapy: Mapping the way. Nat Med, 2004,10(5): 475-480.
119. Santin AD, Bellone S, Gokden M, et al. Vaccination with HPV-18 E7-pulsed dendritic cells in a patient with metastatic cervical cancer. N Engl J Med, 2002, 346(22):1752-1753.
120. Adams M, de Jong A, Havabi H, et al. In vivo induction of HPV 16 specific CTL and T helper responses in patients with advanced cervical cancer using autologous dendritic cells pulsed with tumor lysate. International Papillomavirus Conference, Florianopolis, Brazil, 2001,19: Abs P-99.
121. Adams M, Navabi H, Jasani B, et al. Dendritic cell(DC) based therapy for cervical cancer: Use of DC pulsed with tumor lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly[l]: poly[C12U] (Ampligen). Vaccine, 2003, 21(7-8):787-790.
122. Tobery TW, Smith JF, Kuklin N, et al. Effect of vaccine delivery system on the induction of HPV16Ll-specific humoral and cell-mediated immune responses in immunized rhesus macaques. Vaccine, 2003,21:1539-1547.
123. James Colgrove. The Ethics and Politics of Compulsory HPV Vaccination. The New England Journal of Medicine. December 7,2006.
124. Chapter 5: Updating the natural history of HPV and anogenital cancer. Anna-Barbara Moscicki, Mark Schiffman et al. Vaccine 24S3 (2006) S3/42-S3/51