The role of herpesviruses in development of diseases of the urogenital tract and infertility in women

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Abstract

This review presents the data on the spreading of all known human herpesviruses (НHVs) in female urogenital tract. According to the WHO almost 500 million people worldwide suffer from genital infection caused by НHVs. НHVs were detected in various inflammatory diseases of female upper and lower genital tract (vaginitis and cervicitis), in extrauterine pregnancy (in fallopian tubes), in infertility (cervical channel, endometrium and ovaries). Herpes simplex virus 1 (HSV‑1) was identified for the first time in oocytes after failed in vitro fertilization (IVF). НHVs produce negative effect on the entire reproductive process from conception to childbirth. It was established that HSV, cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6) markedly increase the risk of spontaneous abortion, preterm birth and stillbirth. Intrauterine НHV infection is a major cause of congenital malformations. Data on humoral and cell immunity in genital herpesvirus infections (НHVI) are also reviewed. Intravaginal HSV‑2 infection changes cell composition of vaginal mucosa, i.e., together with cells mobilized from the blood, protective role is performed by resident memory T‑cells (TRM), natural killer cells (NK‑cells) and regulatory T‑cells (Treg) whose function consists in maintaining the balance of the activities of lymphocytes. Constant НHVI spreading is largely explained by transition of primary infection to potentially reactivating latent form, since latent virus is unavailable to immune recognition and medicines. The genome editing system CRISPR/Cas9 can recognize and modify not only active but also latent viruses. The promising pilot results with the use of this system offer the possibility of developing innovative technologies for НHV elimination and НHVI eradication.

About the authors

A. A. Kushch

Ivanovsky Institute of Virology of FSBI «National Research Centre of Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia

Author for correspondence.
Email: vitallku@mail.ru
ORCID iD: 0000-0002-3396-5533

D.Sci. (Biol.), Prof., Head of the laboratory

123098, Moscow

Russian Federation

L. B. Kisteneva

Ivanovsky Institute of Virology of FSBI «National Research Centre of Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia

Email: lborisovna2007@yandex.ru
ORCID iD: 0000-0001-7336-409X
123098, Moscow Russian Federation

R. R. Klimova

Ivanovsky Institute of Virology of FSBI «National Research Centre of Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia

Email: regi.k@mail.ru
ORCID iD: 0000-0002-4147-8444
123098, Moscow Russian Federation

S. G. Cheshik

Ivanovsky Institute of Virology of FSBI «National Research Centre of Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0000-0001-7639-7268
123098, Moscow Russian Federation

References

  1. Тютюнник В.Л., Орджоникидзе Н.В., Зыряева Н.А. Перинатальные аспекты цитомегаловирусной инфекции. Акушерство и гинекология. 2002; (1): 9–11.
  2. Gabrielli L., Losi L., Varani S.L., Lazzarotto T., Eusebi V., Landini M.P. Complete replication of human cytomegalovirus in explants of first trimester human placenta. J. Med. Virol. 2001; 64(4): 499–504. https://doi.org/10.1002/jmv.1077.
  3. Arav-Boger R., Pass R. Viral load in congenital cytomegalovirus infection. Herpes. 2007; 14(1): 17–22.
  4. Marci R., Gentili V., Bortolotti D., Lo Monte G., Caselli E., Bolzani S., et al. Presence of HHV-6A in Endometrial Epithelial Cells from Women with Primary Unexplained Infertility. PLoS One. 2016; 11(7):e0158304. https://doi.org/10.1371/journal.pone.0158304.
  5. Groves M.J. Genital herpes: a review. Am. Fam. Physician. 2016; 93(11): 928–34.
  6. Knipe D.M., Howley P.M., eds. Fields Virology. Philadelphia: Williams & Wilkins; 2013.
  7. Tronstein E., Johnston C., Huang M.L., Selke S., Magaret A., Warren T., et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011; 305(14): 1441–9. https://doi.org/10.1001/jama.2011.420.
  8. Барамзина С.В. Комплексный подход к терапии генитального герпеса. Поликлиника. 2017; (1-3): 38–40.
  9. Ayoub H.H., Chemaitelly H., Abu-Raddad L. Characterizing the transitioning epidemiology of herpes simplex virus type 1 in the USA: model-based predictions. BMC Med. 2019; 17(1): 57. https://doi.org/10.1186/s12916-019-1285-x.
  10. Durukan D., Fairley C.K., Bradshaw C.S., Read T.H., Druce J., Catton M., et al. Increasing proportion of herpes simplex virus type 1 among women and men diagnosed with first-episode anogenital herpes: a retrospective observational study over 14 years in Melbourne, Australia. Sex. Transm. Infect. 2019; 95(4): 307–13. https://doi.org/10.1136/sextrans-2018-053830.
  11. Sukik L., Alyafei M., Harfouche M., Abu-Raddadet L. Herpes simplex virus type 1 epidemiology in Latin America and the Caribbean: Systematic review and meta-analytics. PLoS One. 2019; 14(4):e0215487. https://doi.org/10.1371/journal.pone.0215487.
  12. Silver M.I., Proma P., Sowjanya P. Shedding of Epstein-Barr virus and cytomegalovirus from the genital tract of women in a periurban community in Andhra Pradesh, India. J. Clin. Microbiol. 2011; 49(7): 2435–9. https://doi.org/10.1128/JCM.02206-10.
  13. Thomas R., Macsween K.F., McAulay K., Clutterbuck D., Anderson R., Reid S., et al. Evidence of shared Epstein–Barr viral isolates between sexual partners, and low level EBV in genital secretions. J. Med. Virol. 2006; 78(9): 1204–9. https://doi.org/10.1002/jmv.20682.
  14. Al-Rawahi G.N., Dobson S.R., Scheifele D.W., Rassekh S.R., Murphy D.J. Severe genital ulceration in an acute Epstein–Barr virus infection. Pediatr. Infect. Dis. J. 2011; 30(2): 176–8. https://doi.org/10.1097/INF.0b013e3181f41b2e.
  15. Batwa S.A., Ashshi A.M., Kamfar F.F. Prevalence of cytomegalovirus, and its effect on the expression of inducible and endothelial nitric oxide synthases in Fallopian tubes collected from women with and without ectopic pregnancy. Eur. J. Clin. Microbiol. Infect. Dis. 2016; 35(1): 103–10. https://doi.org/10.1007/s10096-015-2514-7.
  16. Uenaka M., Morizane M., Tanimura K., Deguchi M., Deguchi M., Kanzawa M., et al. Histopathological analysis of placentas with congenital cytomegalovirus infection. Placenta. 2019; 75: 62–7. https://doi.org/10.1016/j.placenta.2019.01.003.
  17. Slyker J., Farquhar C., Atkinson C. Compartmentalized cytomegalovirus replication and transmission in the setting of maternal HIV-1 infection. Clin. Infect. Dis. 2014; 58(4): 564–72. https://doi.org/10.1093/cid/cit727.
  18. Baillargeon J., Piper J., Leach C.T. Epidemiology of human herpesvirus 6 (HHV-6) infection in pregnant and nonpregnant women. J. Clin. Virol. 2000; 16(3): 149–57. https://doi.org/10.1016/s1386-6532(99)00086-4.
  19. Ohashi M., Yoshikawa T., Ihira M. Reactivation of human herpesvirus 6 and 7 in pregnant women. J. Med. Virol. 2002; 67(3): 354–8. https://doi.org/10.1002/jmv.10083.
  20. Coulam C.B., Bilal M., Salazar Garcia M.D. Prevalence of HHV-6 in endometrium from women with recurrent implantation failure. Am. J. Reprod. Immunol. 2018; 80(1): e12862. https://doi.org/10.1111/aji.12862.
  21. Maeda T., Okuno T., Hayashi K., Miyamoto H., Utsunomiya A., Yamada Y., et al. Abortion in human herpesvirus 6 DNA-positive pregnant women. Pediatr. Infect. Dis. J. 1997; 16(12): 1176–7. https://doi.org/10.1097/00006454-199712000-00014.
  22. Cone R.W., Huang M.L., Ashley R., Corey L. Human herpesvirus 6 DNA in peripheral blood cells and saliva from immunocompetent individuals. J. Clin. Microbiol. 1993; 31(5): 1262–7. https://doi.org/10.1128/JCM.31.5.1262-1267.1993.
  23. Мелехина Е.В., Черкасова С.В., Домонова Э.А., Сильвей- строва О.Ю., Кулешов К.В., Гоптарь И.А. и др. Наследуемая хромосомная интеграция Human betaherpesvirus 6B у недоношенных новорождённых. Педиатрия. Журнал им. Г.Н. Сперанского. 2019; 98(2): 28–34. https://doi.org/10.24110/0031-403X-2019-98-2-28-34.
  24. Цинзерлинг В.А., Мельникова В.Ф. Перинатальные инфекции. Практическое руководство. СПб.: Элби-СПб; 2002.
  25. Макаров О.В., Ковальчук Л.В., Ганковская Л.В., Бахарева И.В., Ганковская О.А. Невынашивание беременности, инфекция, врождённый иммунитет. М.: ГЭОТАР-Медиа; 2007.
  26. Weisblum Y., Panet A., Zakay-Rones Z., Vitenshtein A., Haimov-Kochman R., Goldman-Wohlet D. et al. Human cytomegalovirus induces a distinct innate immune response in the maternal-fetal interface. Virology. 2015; 485: 289–96. https://doi.org/10.1016/j.virol.2015.06.023.
  27. Oliveira G.M., Pascoal-Xavier M.A., Moreira D.R., Guimarães V.S., Aguiar R.A., Miranda D.M., et al. Detection of cytomegalovirus, herpes virus simplex, and parvovirus b19 in spontaneous abortion placentas. J. Matern. Fetal Neonatal Med. 2019; 32(5): 768–75. https://doi.org/10.1080/14767058.2017.1391778.
  28. Giakoumelou S., Wheelhouse N., Cuschieri K., Entrican G., Howie S.E., Horne A. The role of infection in miscarriage. Hum. Reprod. Update. 2016; 22(1): 116–33. https://doi.org/10.1093/humupd/dmv041.
  29. Володин Н.Н. Перинатология. Исторические вехи, перспективы развития. Вопросы практической педиатрии. 2006; 1(3): 5–24.
  30. Haahr T., Humaidan P., Elbaek H.O. Vaginal microbiota and in vitro fertilization outcomes: development of a simple diagnostic tool to predict patients at risk of a poor reproductive outcome. J. Infect. Dis. 2019; 219(11): 1809–17. https://doi.org/10.1093/infdis/jiy744.
  31. Чешик С.Г., Кистенева Л.Б. Цитомегаловирусная инфекция и спонтанные аборты у женщин I и II триместров беременности. Вопросы вирусологии. 2016; 61(2): 74–8. https://doi.org/10.18821/0507-4088-2016-61-2-74-78.
  32. Сидельникова В.М., Ходжаева З.С., Агаджанова А.А. Актуальные вопросы невынашивания беременности. М.: 2001.
  33. Shi T.L., Huang L.J., Xiong Y.Q., Zhong Y.Y., Yang J.J., Fu T., et al. The risk of herpes simplex virus and human cytomegalovirus infection during pregnancy upon adverse pregnancy outcomes: A meta-analysis. J. Clin. Virol. 2018; 104: 48–55. https://doi.org/10.1016/j.jcv.2018.04.016.
  34. Wylie K.M., Wylie T.N., Cahill A.G. The vaginal eukaryotic DNA virome and preterm birth. Am. J. Obstet. Gynecol. 2018; 219(2):189.e1-12. https://doi.org/10.1016/j.ajog.2018.04.048.
  35. Eskew A.M., Stout M.J., Bedrick B.S., Riley J.K., Omurtag K.R., Jimenez P.T., et al. Association of the eukaryotic vaginal virome with prophylactic antibiotic exposure and reproductive outcomes in a subfertile population undergoing in vitro fertilisation: a prospective exploratory study. BJOG. 2020; 127(2): 208–16. https://doi.org/10.1111/1471-0528.15951.
  36. Mascarenhas M.N., Cheung H., Mathers C.D., Stevens G.A. Measuring infertility in populations: constructing a standard definition for use with demographic and reproductive health surveys. Popul. Health Metr. 2012; 10(1): 17. https://doi.org/10.1186/1478-7954-10-17.
  37. Медведев Б.И., Зайнетдинова Л.Ф., Теплова С.Н. Микрофлора органов репродуктивной системы у женщин с трубно-перитонеальным бесплодием. Журнал микробиологии, эпидемиологии и иммунобиологии. 2008; 85(3): 58–61.
  38. Wylie K.M., Mihindukulasuriya K.A., Zhou Y., Sodergren E., Storch G.A., Weinstock G.M. Metagenomic analysis of doublestranded DNA viruses in healthy adults. BMC Biol. 2014; 12: 71. https://doi.org/10.1186/s12915-014-0071-7.
  39. Eskew A.M., Stout M.J., Bedrick B.S., Riley J.K., Omurtag K.R., Jimenez P.T., et al. Association of the eukaryotic vaginal virome with prophylactic antibiotic exposure and reproductive outcomes in a subfertile population undergoing in vitro fertilisation: a prospective exploratory study. BJOG. 2020; 127(2): 208–16. https://doi.org/10.1111/1471-0528.15951.
  40. Абдулмеджидова А.Г., Рог К.В., Завалишина Л.Э., Кущ А.А. Интрафолликулярное инфицирование вирусом простого герпеса ооцитов млекопитающих и человека. Вопросы вирусологии. 2014; 59(1): 42–6.
  41. Harwani S.C., Lurain N.S., Zariffard M.R., Spear G.T. Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue. Virol. J. 2007; 4: 133. https://doi.org/10.1186/1743-422X-4-133.
  42. Ross S.A., Boppana S.B. Congenital cytomegalovirus infection: outcome and diagnosis. Semin. Pediatr. Infect. Dis. 2005; 16(1):44–9. https://doi.org/10.1053/j.spid.2004.09.011.
  43. Zariffard M.R., Harwani S.C., Novak R.M., Graham P.J., Ji X., Spear G.T. Trichomonas vaginalis infection activates cells through toll-like receptor 4. Clin. Immunol. 2004; 111(1): 103–7. https://doi.org/10.1016/j.clim.2003.12.008.
  44. Shin H., Kumamoto Y., Gopinath S., Iwasaki A. CD301b+ dendritic cells stimulate tissue-resident memory CD8+ T cells to protect against genital HSV-2. Nat. Commun. 2016; 7: 13346. https://doi.org/10.1038/ncomms13346.
  45. Patel C.D., Backes I.M., Taylor S.A., Jiang Y., Marchant A., Pesola J.M., et al. Maternal immunization confers protection against neonatal herpes simplex mortality and behavioral morbidity. Sci. Transl. Med. 2019; 11(487): eaau6039. https://doi.org/10.1126/scitranslmed.aau6039.
  46. Jenks J.A., Goodwin M.L., Permar S.R. The roles of host and viral antibody Fc receptors in herpes simplex virus (HSV) and human cytomegalovirus (HCMV) infections and immunity. Front. Immunol. 2019; 10: 2110. https://doi.org/10.3389/fimmu.2019.02110.
  47. Posavad C.M., Zhao L., Mueller D.E., Stevens C.E., Huang M.L., Wald A., et al. Persistence of mucosal T-cell responses to herpes simplex virus type 2 in the female genital tract. Mucosal Immunol. 2015; 8(1): 115–26. https://doi.org/10.1038/mi.2014.47.
  48. Schiffer J.T., Abu-Raddad L., Mark K.E. Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. Proc. Natl. Acad. Sci. USA. 2010; 107(44): 18973–8. https://doi.org/10.1073/pnas.1006614107.
  49. Oh J.E., Iijima N., Song E., Lu P., Klein J., Jiang R., et al. Migrant memory B cells secrete luminal antibody in the vagina. Nature. 2019; 571(7763): 122–6. https://doi.org/10.1038/s41586-019-1285-1.
  50. Truong N.R., Smith J.B., Sandgren K.J., Cunningham A.L. Mechanisms of immune control of mucosal HSV infection: a guide to rational vaccine design. Front. Immunol. 2019; 10: 373. https://doi.org/10.3389/fimmu.2019.00373.
  51. Оспельникова Т.П., Носеикина Е.М., Гайдерова Л.А., Ершов Ф.И. Терапевтический потенциал препаратов альфа-интерферонов при социально значимых заболеваниях человека вирусной этиологии. Журнал микробиологии, эпидемиологии и иммунобиологии. 2016; 93(5): 109–21.
  52. Srivastava R., Roy S., Coulon P.G., Vahed H., Prakash S., Dhanushkodi N., et al. Therapeutic mucosal vaccination of herpes simplex virus 2-infected guinea pigs with ribonucleotide reductase 2 (RR2) protein boosts antiviral neutralizing antibodies and local tissue-resident CD4+ and CD8+ TRM cells associated with protection against recurrent genital herpes. J. Virol. 2019; 93(9): e02309-18. https://doi.org/10.1128/JVI.02309-18.
  53. Hsu P.D., Lander E.S., Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014; 157(6): 1262–78. https://doi.org/10.1016/j.cell.2014.05.010.
  54. Bi Y., Sun L., Gao D., Ding C., Li Z., Li Y., et al. High-efficiency targeted editing of large viral genomes by RNA-guided nucleases. PLoS Pathog. 2014; 10(5): e1004090. https://doi.org/10.1371/journal.ppat.1004090.
  55. Карпов Д.С., Карпов В.Л., Климова Р.Р., Демидова Н.А., Кущ А.А. Система CRISPR/Cas9, экспрессируемая с плазмиды, подавляет репликацию вируса простого герпеса 1 типа в культуре клеток Vero. Молекулярная биология. 2019; 53(1): 91–100. https://doi.org/10.1134/S0026898419010051.

Copyright (c) 2021 Kushch A.A., Kisteneva L.B., Klimova R.R., Cheshik S.G.

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