Respons imun seluler terhadap antigen E2, E6, dan E7 HPV16: Pemanfaatannya pencegahan dan terapi kanker serviks
DOI:
https://doi.org/10.54957/ijhs.v4i5.1088Kata Kunci:
Human papillomavirus, Immunotherapy, Oncoprotein, Therapeutic vaccineAbstrak
HPV merupakan kelompok virus penyebab kanker serviks. HPV16 menyebabkan 46-63% karsinoma sel skuamosa serviks. HPV16 terdiri dari 3 region siklus sel, yaitu early region (E), long control region (LCR), dan late region (L). Early region yang berasal dari protein E1, E2, E4, E5, E6, dan E7 berperan dalam ekspresi gen virus, replikasi virus, dan siklus hidup virus. Virus akan mengekspresikan protein E1 dan E2 kemudian terjadi delesi, dan sel yang terinfeksi akan berdiferensiasi dan mengekspresikan E6 dan E7. Ekspresi E6 dan E7 akan menurunkan ekspresi TLR9, IFN-1, dan supresi sitokin proinflamasi. Respons imun yang menurun menyebabkan sel yang terinfeksi berdiferensiasi menjadi sel kanker. Vaksinasi profilaksis digunakan sebagai pencegahan dan pengendalian infeksi virus HPV16, tetapi tidak dapat melindungi individu yang sudah terinfeksi dari perkembangan infeksi virus dan sel abnormal. Oleh karena itu, vaksinasi terapeutik diperlukan untuk imunoterapi kanker. Antigen HPV16 yang terdiri dari E2, E6, dan E7 diharapkan menjadi target yang baik. Antigen E2, E6, dan E7 bertujuan untuk mengaktifkan respons imun spesifik yang diperantarai sel untuk memfagositosis sel yang terinfeksi. Antigen diproses oleh sel dendritik dan kemudian disajikan kepada molekul MHC. MHC II akan merangsang respons sel T CD4+ terhadap protein yang akan membantu sel T CD8+ sitotoksik. Antigen disajikan oleh MHC I untuk dipresentasikan ke sel T CD8+ sitotoksik untuk mengeliminasi sel yang terinfeksi. Antigen E2, E6, dan E7 untuk imunoterapi guna mencegah perkembangan sel abnormal sehingga tidak berkembang menjadi kanker.
Referensi
Akira, S., & Takeda, K. (2004). Toll-like receptor signalling. Nature Reviews Immunology, 4(7), 499–511. https://doi.org/10.1038/nri1391
Almeida, A. M., Queiroz, J. A., Sousa, F., & Sousa, Â. (2019). Cervical cancer and HPV infection: ongoing therapeutic research to counteract the action of E6 and E7 oncoproteins. Drug Discovery Today, 24(10), 2044–2057. https://doi.org/10.1016/j.drudis.2019.07.011
Badillo-Godinez, O., Pedroza-Saavedra, A., Valverde-Garduño, V., Bermudez-Morales, V., Maldonado-Gama, M., Leon-Letelier, R., Bonifaz, L. C., Esquivel-Guadarrama, F., & Gutierrez-Xicotencatl, L. (2021). Induction of Therapeutic Protection in an HPV16-Associated Mouse Tumor Model Through Targeting the Human Papillomavirus-16 E5 Protein to Dendritic Cells. Frontiers in Immunology, 12(February), 1–15. https://doi.org/10.3389/fimmu.2021.593161
Balasubramaniam, S. D., Balakrishnan, V., Oon, C. E., & Kaur, G. (2019). Key molecular events in cervical cancer development. Medicina (Lithuania), 55(7). https://doi.org/10.3390/medicina55070384
Bergvall, M., Melendy, T., & Archambault, J. (2013). The E1 proteins. Virology, 445(1–2), 35–56. https://doi.org/10.1016/j.virol.2013.07.020
Bernard, H. U., Burk, R. D., Chen, Z., van Doorslaer, K., Hausen, H. zur, & de Villiers, E. M. (2010). Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology, 401(1), 70–79. https://doi.org/10.1016/j.virol.2010.02.002
Burk, R. D., Chen, Z., Saller, C., Tarvin, K., Carvalho, A. L., Scapulatempo-Neto, C., Silveira, H. C., Fregnani, J. H., Creighton, C. J., Anderson, M. L., Castro, P., Wang, S. S., Yau, C., Benz, C., Gordon Robertson, A., Mungall, K., Lim, L., Bowlby, R., Sadeghi, S., … Mutch, D. (2017). Integrated genomic and molecular characterization of cervical cancer. Nature, 543(7645), 378–384. https://doi.org/10.1038/nature21386
Chabeda, A., Yanez, R. J. R., Lamprecht, R., Meyers, A. E., Rybicki, E. P., & Hitzeroth, I. I. (2018). Therapeutic vaccines for high-risk HPV-associated diseases. Papillomavirus Research, 5(August 2017), 46–58. https://doi.org/10.1016/j.pvr.2017.12.006
Daniel E Shumer, N. J. N. N. P. S. (2017). The current state of therapeutic and T cell-based vaccines against human papillomaviruses. Physiology & Behavior, 176(12), 139–148. https://doi.org/10.1016/j.virusres.2016.12.002.The
de Oliveira, L. M. F., Morale, M. G., Chaves, A. A. M., Demasi, M., & Ho, P. L. (2017). Expression, Polyubiquitination, and Therapeutic Potential of Recombinant E6E7 from HPV16 Antigens Fused to Ubiquitin. Molecular Biotechnology, 59(1), 46–56. https://doi.org/10.1007/s12033-016-9990-6
Decarlo, C. A., Rosa, B., Jackson, R., Niccoli, S., Escott, N. G., & Zehbe, I. (2012). Toll-like receptor transcriptome in the HPV-positive cervical cancer microenvironment. Clinical and Developmental Immunology, 2012. https://doi.org/10.1155/2012/785825
Decarlo, C. A., Severini, A., Edler, L., Escott, N. G., Lambert, P. F., Ulanova, M., & Zehbe, I. (2010). IFN-κ, a novel type i IFN, is undetectable in HPV-positive human cervical keratinocytes. Laboratory Investigation, 90(10), 1482–1491. https://doi.org/10.1038/labinvest.2010.95
Deligeoroglou, E., Giannouli, A., Athanasopoulos, N., Karountzos, V., Vatopoulou, A., Dimopoulos, K., & Creatsas, G. (2013). HPV infection: Immunological aspects and their utility in future therapy. Infectious Diseases in Obstetrics and Gynecology, 2013. https://doi.org/10.1155/2013/540850
Dillon, S., Sasagawa, T., Crawford, A., Prestidge, J., Inder, M. K., Jerram, J., Mercer, A. A., & Hibma, M. (2007). Resolution of cervical dysplasia is associated with T-cell proliferative responses to human papillomavirus type 16 E2. Journal of General Virology, 88(3), 803–813. https://doi.org/10.1099/vir.0.82678-0
Egawa, N., Wang, Q., Griffin, H. M., Murakami, I., Jackson, D., Mahmood, R., & Doorbar, J. (2017). HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions. In PLoS Pathogens (Vol. 13, Issue 3). https://doi.org/10.1371/journal.ppat.1006282
Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D. M., Piñeros, M., Znaor, A., & Bray, F. (2019). Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer, 144(8), 1941–1953. https://doi.org/10.1002/ijc.31937
Garbuglia, A. R., Lapa, D., Sias, C., Capobianchi, M. R., & Del Porto, P. (2020). The Use of Both Therapeutic and Prophylactic Vaccines in the Therapy of Papillomavirus Disease. Frontiers in Immunology, 11(February), 1–14. https://doi.org/10.3389/fimmu.2020.00188
Garcia-Iglesias, T., del Toro-Arreola, A., Albarran-Somoza, B., del Toro-Arreola, S., Sanchez-Hernandez, P. E., Ramirez-Dueñas, M., Balderas-Peña, L. M. A., Bravo-Cuellar, A., Ortiz-Lazareno, P. C., & Daneri-Navarro, A. (2009). Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer, 9, 1–8. https://doi.org/10.1186/1471-2407-9-186
Gheit, T. (2019). Mucosal and cutaneous human papillomavirus infections and cancer biology. Frontiers in Oncology, 9(MAY). https://doi.org/10.3389/fonc.2019.00355
Ghosh, A., Dasgupta, A., Bandyopadhyay, A., Ghosh, T. K., Dalui, R., Biswas, S., Banerjee, U., & Basu, A. (2015). A study of the expression and localization of toll-like receptors 2 and 9 in different grades of cervical intraepithelial neoplasia and squamous cell carcinoma. Experimental and Molecular Pathology, 99(3), 720–724. https://doi.org/10.1016/j.yexmp.2015.11.015
Hacke, K., Rincon-Orozco, B., Buchwalter, G., Siehler, S. Y., Wasylyk, B., Wiesmüller, L., & Rösl, F. (2010). Regulation of MCP-1 chemokine transcription by p53. Molecular Cancer, 9, 1–12. https://doi.org/10.1186/1476-4598-9-82
Hancock, G., Blight, J., Lopez-Camacho, C., Kopycinski, J., Pocock, M., Byrne, W., Price, M. J., Kemlo, P., Evans, R. I., Bloss, A., Saunders, K., Kirton, R., Andersson, M., Hellner, K., Reyes-Sandoval, A., & Dorrell, L. (2019). A multi-genotype therapeutic human papillomavirus vaccine elicits potent T cell responses to conserved regions of early proteins. Scientific Reports, 9(1), 1–12. https://doi.org/10.1038/s41598-019-55014-z
Hancock, G., Hellner, K., & Dorrell, L. (2018). Therapeutic HPV vaccines. Best Practice and Research: Clinical Obstetrics and Gynaecology, 47, 59–72. https://doi.org/10.1016/j.bpobgyn.2017.09.008
Harper, D. M., & DeMars, L. R. (2017). HPV vaccines – A review of the first decade. Gynecologic Oncology, 146(1), 196–204. https://doi.org/10.1016/j.ygyno.2017.04.004
Hasan, U. A., Bates, E., Takeshita, F., Biliato, A., Accardi, R., Bouvard, V., Mansour, M., Vincent, I., Gissmann, L., Iftner, T., Sideri, M., Stubenrauch, F., & Tommasino, M. (2007). TLR9 Expression and Function Is Abolished by the Cervical Cancer-Associated Human Papillomavirus Type 16. The Journal of Immunology, 178(5), 3186–3197. https://doi.org/10.4049/jimmunol.178.5.3186
Hasan, U. A., Zannetti, C., Parroche, P., Goutagny, N., Malfroy, M., Roblot, G., Carreira, C., Hussain, I., Müller, M., Taylor-Papadimitriou, J., Picard, D., Sylla, B. S., Trinchieri, G., Medzhitov, R., & Tommasino, M. (2013). The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter. Journal of Experimental Medicine, 210(7), 1369–1387. https://doi.org/10.1084/jem.20122394
Iijima, N., Goodwin, E. C., DiMaio, D., & Iwasaki, A. (2013). High-risk human papillomavirus E6 inhibits monocyte differentiation to Langerhans cells. Virology, 444(1–2), 257–262. https://doi.org/10.1016/j.virol.2013.06.020
Jabbar, B., Rafique, S., Salo-Ahen, O. M. H., Ali, A., Munir, M., Idrees, M., Mirza, M. U., Vanmeert, M., Shah, S. Z., Jabbar, I., & Rana, M. A. (2018). Antigenic Peptide Prediction From E6 and E7 Oncoproteins of HPV Types 16 and 18 for Therapeutic Vaccine Design Using Immunoinformatics and MD Simulation Analysis. Frontiers in Immunology, 9(December), 3000. https://doi.org/10.3389/fimmu.2018.03000
Jalil, A. T., Al-Khafaji, A. H. D., Karevskiy, A., Dilfy, S. H., & Hanan, Z. K. (2021). Polymerase chain reaction technique for molecular detection of HPV16 infections among women with cervical cancer in Dhi-Qar Province. Materials Today: Proceedings, May. https://doi.org/10.1016/j.matpr.2021.05.211
James, C. D., Fontan, C. T., Otoa, R., Das, D., Prabhakar, A. T., Wang, X., Bristol, M. L., & Morgan, I. M. (2020). Innate Immune Gene Transcription. Msphere, 5(1), 1–15. https://doi.org/10.1128/mSphere.00828-19
Jimenez-Perez, M. I., Jave-Suarez, L. F., Ortiz-Lazareno, P. C., Bravo-Cuellar, A., Gonzalez-Ramella, O., Aguilar-Lemarroy, A., Hernandez-Flores, G., Pereira-Suarez, A. L., Daneri-Navarro, A., & del Toro-Arreola, S. (2012). Cervical cancer cell lines expressing NKG2D-ligands are able to down-modulate the NKG2D receptor on NKL cells with functional implications. BMC Immunology, 13. https://doi.org/10.1186/1471-2172-13-7
Jo, E. K., Kim, J. K., Shin, D. M., & Sasakawa, C. (2016). Molecular mechanisms regulating NLRP3 inflammasome activation. Cellular and Molecular Immunology, 13(2), 148–159. https://doi.org/10.1038/cmi.2015.95
Kantang, W., Chunsrivirot, S., Muangsin, N., Poovorawan, Y., & Krusong, K. (2016). Design of peptides as inhibitors of human papillomavirus 16 transcriptional regulator E1–E2. Chemical Biology and Drug Design, May, 475–484. https://doi.org/10.1111/cbdd.12790
Karim, R., Tummers, B., Meyers, C., Biryukov, J. L., Alam, S., Backendorf, C., Jha, V., Offringa, R., van Ommen, G. J. B., Melief, C. J. M., Guardavaccaro, D., Boer, J. M., & van der Burg, S. H. (2013). Human Papillomavirus (HPV) Upregulates the Cellular Deubiquitinase UCHL1 to Suppress the Keratinocyte’s Innate Immune Response. PLoS Pathogens, 9(5). https://doi.org/10.1371/journal.ppat.1003384
Khan, K. H. (2013). DNA vaccines: Roles against diseases. Germs, 3(1), 26–35. https://doi.org/10.11599/germs.2013.1034
Kim, H. J., & Kim, H. J. (2017). Current status and future prospects for human papillomavirus vaccines. Archives of Pharmacal Research, 40(9), 1050–1063. https://doi.org/10.1007/s12272-017-0952-8
Kim, J. H., Kang, T. H., Noh, K. H., Bae, H. C., Kim, S. H., Yoo, Y. Do, Seong, S. Y., & Kim, T. W. (2009). Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8+ T cell-mediated cell death. Immunology Letters, 122(1), 58–67. https://doi.org/10.1016/j.imlet.2008.12.006
Kudela, E., Liskova, A., Samec, M., Koklesova, L., Holubekova, V., Rokos, T., Kozubik, E., Pribulova, T., Zhai, K., Busselberg, D., Kubatka, P., & Biringer, K. (2021). The interplay between the vaginal microbiome and innate immunity in the focus of predictive, preventive, and personalized medical approach to combat HPV-induced cervical cancer. EPMA Journal, 12(2), 199–220. https://doi.org/10.1007/s13167-021-00244-3
Kyrgiou, M., Athanasiou, A., Paraskevaidi, M., Mitra, A., Kalliala, I., Martin-Hirsch, P., Arbyn, M., Bennett, P., & Paraskevaidis, E. (2016). Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: Systematic review and meta-analysis. BMJ (Online), 354. https://doi.org/10.1136/bmj.i3633
Lee, S. J., Yang, A., Wu, T., & Hung, C. F. (2016). Immunotherapy for human papillomavirus-associated. Journal of Gynecologic Oncology, 27(5), 1–17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944018/pdf/jgo-27-e51.pdf
Leticia, S. M. M. (2020). Cloning, Expression, and Purification of the rE2 Protein Human Papillomavirus type 16. Protein Research & Bioinformatics, November, 1–5. https://doi.org/10.24966/prb-1545/100012
Ma, B., Maraj, B., Tran, N. P., Knoff, J., Chen, A., Alvarez, R. D., Hung, C. F., & Wu, T. C. (2012). Emerging human papillomavirus vaccines. Expert Opinion on Emerging Drugs, 17(4), 469–492. https://doi.org/10.1517/14728214.2012.744393
Manickam, A., Sivanandham, M., & Tourkova, I. L. (2007). Immunological role of dendritic cells in cervical cancer. Advances in Experimental Medicine and Biology, 601(Tindle 2002), 155–162. https://doi.org/10.1007/978-0-387-72005-0_16
Mavrommatis, E., Lytsikas-Sarlis, P., & Troupis, T. (2021). Historical pearls of hpv research: From condyloma to cervical cancer. Infezioni in Medicina, 29(2), 278–283.
Molto, E., & Sheldrick, P. (2018). Paleo-oncology in the Dakhleh Oasis, Egypt: Case studies and a paleoepidemiological perspective. International Journal of Paleopathology, 21(September 2017), 96–110. https://doi.org/10.1016/j.ijpp.2018.02.003
Moody, C. A., & Laimins, L. A. (2010). Human papillomavirus oncoproteins: Pathways to transformation. Nature Reviews Cancer, 10(8), 550–560. https://doi.org/10.1038/nrc2886
Pal, A., & Kundu, R. (2020). Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy. Frontiers in Microbiology, 10(January). https://doi.org/10.3389/fmicb.2019.03116
Pang, C. L., & Thierry, F. (2013). Human papillomavirus proteins as prospective therapeutic targets. Microbial Pathogenesis, 58, 55–65. https://doi.org/10.1016/j.micpath.2012.11.002
Patente, T. A., Pinho, M. P., Oliveira, A. A., Evangelista, G. C. M., Bergami-Santos, P. C., & Barbuto, J. A. M. (2019). Human dendritic cells: Their heterogeneity and clinical application potential in cancer immunotherapy. Frontiers in Immunology, 10(JAN), 1–18. https://doi.org/10.3389/fimmu.2018.03176
Ramakrishnan, V., Haydu, C. De, Wilkinson, P., Hooda, U., & Giri, B. (2021). Minnelide , a prodrug , inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb. 11(5), 2202–2214.
Roman, A., & Munger, K. (2013). The papillomavirus E7 proteins. Virology, 445(1–2), 138–168. https://doi.org/10.1016/j.virol.2013.04.013
Sasagawa, T., Takagi, H., & Makinoda, S. (2012). Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. Journal of Infection and Chemotherapy, 18(6), 807–815. https://doi.org/10.1007/s10156-012-0485-5
Sato, Y., Goto, Y., Narita, N., & Hoon, D. S. B. (2009). Cancer cells expressing toll-like receptors and the tumor microenvironment. Cancer Microenvironment, 2(SUPPL. 1). https://doi.org/10.1007/s12307-009-0022-y
Sayour, E. J., & Mitchell, D. A. (2017). Manipulation of Innate and Adaptive Immunity through Cancer Vaccines. Journal of Immunology Research, 2017. https://doi.org/10.1155/2017/3145742
Serrano, B., Brotons, M., Bosch, F. X., & Bruni, L. (2018). Epidemiology and burden of HPV-related disease. Best Practice and Research: Clinical Obstetrics and Gynaecology, 47, 14–26. https://doi.org/10.1016/j.bpobgyn.2017.08.006
Sher, Y.-P., Lee, C., Liu, S.-Y., Chen, I.-H., Lee, M.-H., Chiu, F.-F., Leng, C.-H., & Liu, S.-J. (2018). A therapeutic vaccine targeting HPV E6/E7 with intrinsic Toll-like receptor 2 agonist activity induces antitumor immunity. American Journal of Cancer Research, 8(12), 2528–2537.
Stanley, M. A. (2012). Epithelial cell responses to infection with human papillomavirus. Clinical Microbiology Reviews, 25(2), 215–222. https://doi.org/10.1128/CMR.05028-11
Sushil Kumar, S. V. A., Manash Biswas, B., & Jose, T. (2015). HPV vaccine: Current status and future directions. Medical Journal Armed Forces India, 71(2), 171–177. https://doi.org/10.1016/j.mjafi.2015.02.006
Syrjänen, S., & Syrjänen, K. (2008). The history of papillomavirus research. Central European Journal of Public Health, 16(SUPPL.), S7–S13. https://doi.org/10.21101/cejph.b0040
Torres-Poveda, K., Bahena-Román, M., Madrid-González, C., Burguete-García, A. I., Bermúdez-Morales, V. H., Peralta-Zaragoza, O., & Madrid-Marina, V. (2014). Role of IL-10 and TGF-β1 in local immunosuppression in HPV-associated cervical neoplasia. World Journal of Clinical Oncology, 5(4), 753–763. https://doi.org/10.5306/wjco.v5.i4.753
Van Doorslaer, K., Tan, Q., Xirasagar, S., Bandaru, S., Gopalan, V., Mohamoud, Y., Huyen, Y., & McBride, A. A. (2013). The Papillomavirus Episteme: A central resource for papillomavirus sequence data and analysis. Nucleic Acids Research, 41(D1), 571–578. https://doi.org/10.1093/nar/gks984
Vande Pol, S. B., & Klingelhutz, A. J. (2013). Papillomavirus E6 oncoproteins. Virology, 445(1–2), 115–137. https://doi.org/10.1016/j.virol.2013.04.026
Wang, X., Che, Y., Chen, B., Zhang, Y., Nakagawa, M., & Wang, X. (2018). Evaluation of immune responses induced by a novel human papillomavirus type 16 E7 peptide-based vaccine with Candida skin test reagent as an adjuvant in C57BL/6 mice. International Immunopharmacology, 56(77), 249–260. https://doi.org/10.1016/j.intimp.2018.01.037
Welters, M. J. P., Kenter, G. G., Piersma, S. J., Vloon, A. P. G., Löwik, M. J. G., Berends-van Der Meer, D. M. A., Drijfhout, J. W., Valentijn, A. R. P. M., Wafelman, A. R., Oostendorp, J., Fleuren, G. J., Offringa, R., Melief, C. J. M., & Van Der Burg, S. H. (2008). Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clinical Cancer Research, 14(1), 178–187. https://doi.org/10.1158/1078-0432.CCR-07-1880
Woo, Y. L., Van Den Hende, M., Sterling, J. C., Coleman, N., Crawford, R. A. F., Kwappenberg, K. M. C., Stanley, M. A., & Van Der Burg, S. H. (2010). A prospective study on the natural course of low-grade squamous intraepithelial lesions and the presence of HPV16 E2-, E6- And E7-specific T-cell responses. International Journal of Cancer, 126(1), 133–141. https://doi.org/10.1002/ijc.24804
World Health Organization. (2020). Human papillomavirus (HPV) and cervical cancer. https://www.who.int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer
Wu, C. Y., Monie, A., Pang, X., Hung, C. F., & Wu, T. C. (2010). Improving therapeutic HPV peptide-based vaccine potency by enhancing CD4+ T help and dendritic cell activation. Journal of Biomedical Science, 17(1), 1–10. https://doi.org/10.1186/1423-0127-17-88
Yang, A., Farmer, E., Wu, T. C., & Hung, C. F. (2016). Perspectives for therapeutic HPV vaccine development. Journal of Biomedical Science, 23(1), 1–19. https://doi.org/10.1186/s12929-016-0293-9
Yao, Y., Huang, W., Yang, X., Sun, W., Liu, X., Cun, W., & Ma, Y. (2013). HPV-16 E6 and E7 protein T cell epitopes prediction analysis based on distributions of HLA-A loci across populations: An in silico approach. Vaccine, 31(18), 2289–2294. https://doi.org/10.1016/j.vaccine.2013.02.065
Zur Hausen, H. (2002). Papillomaviruses and cancer: From basic studies to clinical application. Nature Reviews Cancer, 2(5), 342–350. https://doi.org/10.1038/nrc798
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