Вирус папилломы человека: от понимания иммунопатогенеза к рациональной тактике ведения

1. Вакцины против папилломавирусной инфекции человека: документ по позиции ВОЗ, октябрь 2014 г. Еженедельный эпидемиологический бюллетень. 2014; 89 (43): 465–92. / Vakciny protiv papillomavirusnoj infekcii cheloveka: dokument po pozicii VOZ, oktyabr' 2014 g. Ezhenedel'nyj epidemiologicheskij byulleten'. 2014; 89 (43): 465–92. [in Russian]
2. Bosch FX, Broker TR, Forman D et al. Comprehensive control of human papillomavirus infections and related diseases. Vaccine 2013; 31 (5): 1–31.
3. Park IU, Introcaso C, Dunne EF. Human Papillomavirus and Genital Warts: A Review of the Evidence for the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. Clin Infect Dis 2015; 61 (8): 849–55.
4. Patel H, Wagner M, Singhal P et al. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis 2013; 13: 39.
5. Lacey CJ, Woodhall SC, Wikstrom A et al. 2012 European guideline for the management of anogenital warts. J Eur Acad Dermatol Venereol 2013; 27 (3): 263–70.
6. Bruni L et al. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in the World. Summary Report 2014; 2014: 12–8.
7. Состояние онкологической помощи населению России в 2016 году. Под ред. А.Д.Каприна, В.В.Старинского, Г.В.Петровой. М.: МНИОИ им. П.А.Герцена – филиал ФГБУ НМИЦР, 2017. / Sostoyanie onkologicheskoj pomoshchi naseleniyu Rossii v 2016 godu. Pod red. A.D.Kaprina, V.V.Starinskogo, G.V.Petrovoj. M.: MNIOI im. P.A.Gercena – filial FGBU NMICR, 2017. [in Russian]
8. Westrich JA, Warren CJ, Pyeon D. Evasion of Host Immune Defenses by Human Papillomavirus. Virus Res 2017; 231: 21–33. DOI: 10.1016/j.virusres.2016.11.023
9. Den Boon JA, Pyeon D, Wang SS et al. Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. Proc Natl Acad Sci USA 2015; 112: E3255–3264.
10. Huibregtse JM, Scheffner M, Howley PM. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J 1991; 10: 4129–35.
11. Hebner C, Beglin M, Laimins LA. Human papillomavirus E6 proteins mediate resistance to interferon- induced growth arrest through inhibition of p53 acetylation. J Virol 2007; 81: 12740–7. DOI: 10.1128/JVI.00987-07
12. Стерн П.Л., Китченер Г.С. Пер с анг. Под общ. ред. Г.Т.Сухих, В.Н.Прилепской. Вакцина для профилактики РШМ. М.: МЕДпресс-информ, 2009. / Stern P.L., Kitchener G.S. Per s ang. Pod obshch. red. G.T.Suhih, V.N.Prilepskoj. Vakcina dlya profilaktiki RShM. M.: MEDpress-inform, 2009. [in Russian]
13. Ho GYF, Bierman R, Beardsley L et al. Natural history of cervicovaginal HPV infections in young women. NEJM 1998; 338: 423–8.
14. Andersen AS, Koldjaer Solling AS, Ovesen T et al. The interplay between HPV and host immunity in head and neck squamous cell carcinoma. Int J Cancer 2014; 134 (12): 2755–63.
15. Disaia PJ, Creasman WT. Клиническая онкогинекология. Пер. с англ. Под ред. Е.Г.Новиковой. М.: Рид Элсивер, 2011. Т. 1. / Disaia PJ, Creasman WT. Klinicheskaya onkoginekologiya. Per. s angl. Pod red. E.G.Novikovoj. M.: Rid Elsiver, 2011. T. 1. [in Russian]
16. Киселев В.И., Ашрафян Л.А., Киселев О.И. Этиологическая роль вируса папилломы человека в развитии рака шейки матки: генетические и патогенетические механизмы, возможности терапии и профилактики. Гинекология. 2004; 6 (4): 174–80. / Kiselev V.I., Ashrafyan L.A., Kiselev O.I. Etiologicheskaya rol' virusa papillomy cheloveka v razvitii raka shejki matki: geneticheskie i patogeneticheskie mekhanizmy, vozmozhnosti terapii i profilaktiki. Gynecology. 2004; 6 (4): 174–80. [in Russian]
17. Tavares-Murta BM, de Resende AD, Cunha FQ, Murta EF. Local profile of cytokines and nitric oxide in patients with bacterial vaginosis and cervical intraepithelial neoplasia. Eur J Obstet Gynecol Reprod Biol 2008; 138: 93–9.
18. Frazer IH. Interaction of human papillomaviruses with the host immune system: a well evolved relationship. Virology 2009; 384 (2): 410–4. DOI: 10.1016/j.virol.2008.10.004
19. Xiao Yang, Yanxiang Cheng, Chunsheng Li. The role of TLRs in cervical cancer with HPV infection: a review. Signal Transduction and Targeted Therapy 2017; 2: e17055. DOI: 10.1038/sigtrans.2017.55
20. Nees M, Geoghegan JM, Hyman T et al. Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kappaB-responsive genes in cervical keratinocytes.  J Virol 2001; 75: 4283–96.
21. Yang X, Lu L. Expression of HPV-16 E6 protein and p53 inactivation increases the uterine cervical cancer invasion. Drug Res (Stuttg) 2015; 65: 70–3.
22. Hong S, Laimonis A. Laimins. Manipulation of the innate immune response by human papillomaviruses. Shiyuan Virus Res 2017; 231: 34–40. DOI: 10.1016/j.virusres.2016.11.004
23. Niebler M, Qian X, Höfler D et al. Post-translational control of IL-1b via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53. PLoS Pathog 2013; 9: e1003536. DOI: 10.1371 /journal.ppat.1003536
24. Dionne KR, Zhuang Y, Leser JS et al. Daxx upregulation within the cytoplasm of reovirus-infected cells is mediated by interferon and contributes to apoptosis. J Virol 2013; 87: 3447–60.
25. Cicchini L, Westrich JA, Xu T et al. Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14. MBio 2016; 7: e00270–16. DOI: 10.1128/mBio.00270-16
26. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008; 454: 436–44.
27. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34: 637–50.
28. Godfroy JI, Roostan M, Moroz YS et al. Isolated Toll-like receptor transmembrane domains are capable of oligomerization. PLoS One 2012; 7: e48875.
29. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science 2010; 327: 291–5.
30. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 2005; 17: 1–14.
31. Ravishankar RM, Goh KL, Leow AH et al. Polymorphisms at Locus 4p14 of Toll-Like Receptors TLR-1 and TLR-10 Confer Susceptibility to Gastric Carcinoma in Helicobacter pylori Infection. PLoS One 2015; 10: e0141865.
32. Xiao J, Guo Q, Wang X et al. Study on the expression and signification of TLR4/NO pathway in cervical tumorigenesis with high risk HPV infection. Zhonghua Fu Chan Ke Za Zhi 2015; 50: 41–7.
33. Rahkola P, Vaisanen-Tommiska M, Tuomikoski P et al. Cervical nitric oxide release and persistence of high-risk human papillomavirus in women. Int J Cancer 2011; 128: 2933–7.
34. Daud II, Scott ME, Ma Y et al. Association between toll-like receptor expression and human papillomavirus type 16 persistence. Int J Cancer 2011; 128: 879–86.
35. Hasimu A, Ge L, Li QZ et al. Expressions of Toll-like receptors 3, 4, 7, and 9 in cervical lesions and their correlation with HPV16 infection in Uighur women. Chin J Cancer 2011; 30: 344–50.
36. Yu L, Wang L, Li M et al. Expression of toll-like receptor 4 is down-regulated during progression of cervical neoplasia. Cancer Immunol Immunother 2010; 59: 1021–8.
37. Yanxiang Cheng GC, Wang X, Huang Y et al. TLR4 may accelerate hypoxia reaction to promote the occurrence and progress of cervical lesions by infected pathogenic microorganisms other than HPV. J Cancer Ther 2013; 4: 549–53.
38. Fiedler M, Muller-Holzner E, Viertler HP et al. High level HPV-16 E7 oncoprotein expression correlates with reduced pRb-levels in cervical biopsies. FASEB J 2004; 18 (10): 1120–2.
39. Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 1990; 248: 76–9.
40. De Sanjose S et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective crosssectional worldwide study. Lancet Oncol 2010; 11: 1048–56.
41. Majewska A, Lasek W, Janyst M et al In Vitro inhibition of HHV-1 Replication by inosine pranobex and interferon-a. Acta Pol Pharm 2016; 73 (3): 637–44.
42. Lasek W, Janyst M, Wolny R et al. Immunomodulatory effects of inosine pranobex on cytokine production by human lymphocytes. Acta Pharm 2015; 65 (2): 171–80.
43. Tay SK. Efficacy of inosine pranobex oral therapy in subclinical human papillomavirus infection of vulva: a randomized double-blinded placebo controlled study. Int J STD AIDS 1996; 7 (4): 276–80.
44. Забелев А.В., Долматова О.К., Сивоконева Е.Н. и др. Результаты кольпоскопического скрининга и опыт применения Изопринозина в лечении папилломавирусных поражений шейки матки. Фарматека. 2005; 3: 72–5. / Zabelev A.V., Dolmatova O.K., Sivokoneva E.N. i dr. Rezul'taty kol'poskopicheskogo skrininga i opyt primeneniya Izoprinozina v lechenii papillomavirusnyh porazhenij shejki matki. Farmateka. 2005; 3: 72–5. [in Russian]
45. Потапов ВА., Демченко Т.В., Стрельцова ТР. и др. Клинико-лабораторная оценка эффективности Изопринозина в лечении папилломавирусной инфекции, ассоциированной с цервикальной интраэпителиальной неоплазией. Репродуктивное здоровье женщин. 2006; 25 (1): 134–5. / Potapov VA., Demchenko T.V., Strel'cova TR. i dr. Kliniko-laboratornaya ocenka effektivnosti Izoprinozina v lechenii papillomavirusnoj infekcii, associirovannoj s cervikal'noj intraepitelial'noj neoplaziej. Reproduktivnoe zdorov'e zhenshchin. 2006; 25 (1): 134–5. [in Russian]
46. Прилепская В.Н., Роговская С.И. Возможности Изопринозина в лечении хронических цервицитов и вагинитов. Рус. мед. журн. 2008; 16 (1): 5–9. / Prilepskaya V.N., Rogovskaya S.I. Vozmozhnosti Izoprinozina v lechenii hronicheskih cervicitov i vaginitov. Rus. med. zhurn. 2008; 16 (1): 5–9. [in Russian]
47. Линаск Л.И., Григорьева Е.Е. Опыт применения Изопринозина при заболеваниях шейки матки на фоне папилломавирусной инфекции у подростков и молодых женщин. Рус. мед. журн. 2008; 16 (19): 1221. / Linask L.I., Grigor'eva E.E. Opyt primeneniya Izoprinozina pri zabolevaniyah shejki matki na fone papillomavirusnoj infekcii u podrostkov i molodyh zhenshchin. Rus. med. zhurn. 2008; 16 (19): 1221. [in Russian]

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1. Vakciny protiv papillomavirusnoj infekcii cheloveka: dokument po pozicii VOZ, oktyabr' 2014 g. Ezhenedel'nyj epidemiologicheskij byulleten'. 2014; 89 (43): 465–92. [in Russian]
2. Bosch FX, Broker TR, Forman D et al. Comprehensive control of human papillomavirus infections and related diseases. Vaccine 2013; 31 (5): 1–31.
3. Park IU, Introcaso C, Dunne EF. Human Papillomavirus and Genital Warts: A Review of the Evidence for the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. Clin Infect Dis 2015; 61 (8): 849–55.
4. Patel H, Wagner M, Singhal P et al. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis 2013; 13: 39.
5. Lacey CJ, Woodhall SC, Wikstrom A et al. 2012 European guideline for the management of anogenital warts. J Eur Acad Dermatol Venereol 2013; 27 (3): 263–70.
6. Bruni L et al. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in the World. Summary Report 2014; 2014: 12–8.
7. Sostoyanie onkologicheskoj pomoshchi naseleniyu Rossii v 2016 godu. Pod red. A.D.Kaprina, V.V.Starinskogo, G.V.Petrovoj. M.: MNIOI im. P.A.Gercena – filial FGBU NMICR, 2017. [in Russian]
8. Westrich JA, Warren CJ, Pyeon D. Evasion of Host Immune Defenses by Human Papillomavirus. Virus Res 2017; 231: 21–33. DOI: 10.1016/j.virusres.2016.11.023
9. Den Boon JA, Pyeon D, Wang SS et al. Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. Proc Natl Acad Sci USA 2015; 112: E3255–3264.
10. Huibregtse JM, Scheffner M, Howley PM. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J 1991; 10: 4129–35.
11. Hebner C, Beglin M, Laimins LA. Human papillomavirus E6 proteins mediate resistance to interferon- induced growth arrest through inhibition of p53 acetylation. J Virol 2007; 81: 12740–7. DOI: 10.1128/JVI.00987-07
12. Stern P.L., Kitchener G.S. Per s ang. Pod obshch. red. G.T.Suhih, V.N.Prilepskoj. Vakcina dlya profilaktiki RShM. M.: MEDpress-inform, 2009. [in Russian]
13. Ho GYF, Bierman R, Beardsley L et al. Natural history of cervicovaginal HPV infections in young women. NEJM 1998; 338: 423–8.
14. Andersen AS, Koldjaer Solling AS, Ovesen T et al. The interplay between HPV and host immunity in head and neck squamous cell carcinoma. Int J Cancer 2014; 134 (12): 2755–63.
15. Disaia PJ, Creasman WT. Klinicheskaya onkoginekologiya. Per. s angl. Pod red. E.G.Novikovoj. M.: Rid Elsiver, 2011. T. 1. [in Russian]
16. Kiselev V.I., Ashrafyan L.A., Kiselev O.I. Etiologicheskaya rol' virusa papillomy cheloveka v razvitii raka shejki matki: geneticheskie i patogeneticheskie mekhanizmy, vozmozhnosti terapii i profilaktiki. Gynecology. 2004; 6 (4): 174–80. [in Russian]
17. Tavares-Murta BM, de Resende AD, Cunha FQ, Murta EF. Local profile of cytokines and nitric oxide in patients with bacterial vaginosis and cervical intraepithelial neoplasia. Eur J Obstet Gynecol Reprod Biol 2008; 138: 93–9.
18. Frazer IH. Interaction of human papillomaviruses with the host immune system: a well evolved relationship. Virology 2009; 384 (2): 410–4. DOI: 10.1016/j.virol.2008.10.004
19. Xiao Yang, Yanxiang Cheng, Chunsheng Li. The role of TLRs in cervical cancer with HPV infection: a review. Signal Transduction and Targeted Therapy 2017; 2: e17055. DOI: 10.1038/sigtrans.2017.55
20. Nees M, Geoghegan JM, Hyman T et al. Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kappaB-responsive genes in cervical keratinocytes.  J Virol 2001; 75: 4283–96.
21. Yang X, Lu L. Expression of HPV-16 E6 protein and p53 inactivation increases the uterine cervical cancer invasion. Drug Res (Stuttg) 2015; 65: 70–3.
22. Hong S, Laimonis A. Laimins. Manipulation of the innate immune response by human papillomaviruses. Shiyuan Virus Res 2017; 231: 34–40. DOI: 10.1016/j.virusres.2016.11.004
23. Niebler M, Qian X, Höfler D et al. Post-translational control of IL-1b via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53. PLoS Pathog 2013; 9: e1003536. DOI: 10.1371 /journal.ppat.1003536
24. Dionne KR, Zhuang Y, Leser JS et al. Daxx upregulation within the cytoplasm of reovirus-infected cells is mediated by interferon and contributes to apoptosis. J Virol 2013; 87: 3447–60.
25. Cicchini L, Westrich JA, Xu T et al. Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14. MBio 2016; 7: e00270–16. DOI: 10.1128/mBio.00270-16
26. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008; 454: 436–44.
27. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34: 637–50.
28. Godfroy JI, Roostan M, Moroz YS et al. Isolated Toll-like receptor transmembrane domains are capable of oligomerization. PLoS One 2012; 7: e48875.
29. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science 2010; 327: 291–5.
30. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 2005; 17: 1–14.
31. Ravishankar RM, Goh KL, Leow AH et al. Polymorphisms at Locus 4p14 of Toll-Like Receptors TLR-1 and TLR-10 Confer Susceptibility to Gastric Carcinoma in Helicobacter pylori Infection. PLoS One 2015; 10: e0141865.
32. Xiao J, Guo Q, Wang X et al. Study on the expression and signification of TLR4/NO pathway in cervical tumorigenesis with high risk HPV infection. Zhonghua Fu Chan Ke Za Zhi 2015; 50: 41–7.
33. Rahkola P, Vaisanen-Tommiska M, Tuomikoski P et al. Cervical nitric oxide release and persistence of high-risk human papillomavirus in women. Int J Cancer 2011; 128: 2933–7.
34. Daud II, Scott ME, Ma Y et al. Association between toll-like receptor expression and human papillomavirus type 16 persistence. Int J Cancer 2011; 128: 879–86.
35. Hasimu A, Ge L, Li QZ et al. Expressions of Toll-like receptors 3, 4, 7, and 9 in cervical lesions and their correlation with HPV16 infection in Uighur women. Chin J Cancer 2011; 30: 344–50.
36. Yu L, Wang L, Li M et al. Expression of toll-like receptor 4 is down-regulated during progression of cervical neoplasia. Cancer Immunol Immunother 2010; 59: 1021–8.
37. Yanxiang Cheng GC, Wang X, Huang Y et al. TLR4 may accelerate hypoxia reaction to promote the occurrence and progress of cervical lesions by infected pathogenic microorganisms other than HPV. J Cancer Ther 2013; 4: 549–53.
38. Fiedler M, Muller-Holzner E, Viertler HP et al. High level HPV-16 E7 oncoprotein expression correlates with reduced pRb-levels in cervical biopsies. FASEB J 2004; 18 (10): 1120–2.
39. Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 1990; 248: 76–9.
40. De Sanjose S et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective crosssectional worldwide study. Lancet Oncol 2010; 11: 1048–56.
41. Majewska A, Lasek W, Janyst M et al In Vitro inhibition of HHV-1 Replication by inosine pranobex and interferon-a. Acta Pol Pharm 2016; 73 (3): 637–44.
42. Lasek W, Janyst M, Wolny R et al. Immunomodulatory effects of inosine pranobex on cytokine production by human lymphocytes. Acta Pharm 2015; 65 (2): 171–80.
43. Tay SK. Efficacy of inosine pranobex oral therapy in subclinical human papillomavirus infection of vulva: a randomized double-blinded placebo controlled study. Int J STD AIDS 1996; 7 (4): 276–80.
44. Zabelev A.V., Dolmatova O.K., Sivokoneva E.N. i dr. Rezul'taty kol'poskopicheskogo skrininga i opyt primeneniya Izoprinozina v lechenii papillomavirusnyh porazhenij shejki matki. Farmateka. 2005; 3: 72–5. [in Russian]
45. Potapov VA., Demchenko T.V., Strel'cova TR. i dr. Kliniko-laboratornaya ocenka effektivnosti Izoprinozina v lechenii papillomavirusnoj infekcii, associirovannoj s cervikal'noj intraepitelial'noj neoplaziej. Reproduktivnoe zdorov'e zhenshchin. 2006; 25 (1): 134–5. [in Russian]
46. Prilepskaya V.N., Rogovskaya S.I. Vozmozhnosti Izoprinozina v lechenii hronicheskih cervicitov i vaginitov. Rus. med. zhurn. 2008; 16 (1): 5–9. [in Russian]
47. Linask L.I., Grigor'eva E.E. Opyt primeneniya Izoprinozina pri zabolevaniyah shejki matki na fone papillomavirusnoj infekcii u podrostkov i molodyh zhenshchin. Rus. med. zhurn. 2008; 16 (19): 1221. [in Russian]

А.Л.Тихомиров*1, С.И.Сарсания2, Г.А.Филатова1

1. ФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И.Евдокимова» Минздрава России. 127473, Россия, Москва, ул. Делегатская, д. 20, стр. 1;
2. Клиника «Санта-Мария». 127051, Россия, Москва, Цветной б-р, д. 25, стр. 5
*tikhomiroval@yandex.ru

________________________________________________

A.L.Tikhomirov*1, S.I.Sarsaniya2, G.A.Filatova1

1. A.I.Evdokimov Moscow State University of Medicine and Dentistry of the Ministry of Health of the Russian Federation. 127473, Russian Federation, Moscow, ul. Delegatskaia, d. 20, str. 1;
2. Santa Maria clinic. 127051, Russian Federation, Moscow, Tsvetnoy b-r, d. 25, str. 5
* tikhomiroval@yandex.ru