Zika virus (ZIKV) is a re-emerging mosquito-transmitted flavivirus associated with congenital abnormalities in newborns and with Guillain–Barré syndrome in adults. The virus can also be sexually transmitted and can persist in the male genital tract. Studies evaluating the kinetics of ZIKV in seminal shedding of men who have been infected, as well as in animal and cellular models of infection, have shown that, in addition to the testis and epididymis, the prostate and seminal vesicles could also be involved in persistent ZIKV infection. Additionally, some studies have reported that men infected with ZIKV can present with genitourinary symptoms such as haematospermia, prostatitis, painful ejaculation, penile discharge, and oligospermia; however, little is known about the effect of ZIKV on fertility. Understanding the mechanisms that underlie persistent ZIKV infections in men is crucial to developing guidelines, effective vaccines, and therapies.
Zika virus (ZIKV) is sexually transmitted and can induce male subfertility or infertility via multiple pathophysiological mechanisms.
ZIKV can impair sperm parameters and functions when localized in the male genital tract.
The role of ZIKV in the male genital tract remains unclear and further studies of ZIKV in semen and other male genital sites are required to determine the true effect of this pathogen on male fertility.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
The impact of male factors and their correct and early diagnosis in the infertile couple's pathway: 2021 perspectives
Journal of Endocrinological Investigation Open Access 29 March 2022
Middle East Fertility Society Journal Open Access 21 June 2021
Epididymal epithelium propels early sexual transmission of Zika virus in the absence of interferon signaling
Nature Communications Open Access 29 April 2021
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Petersen, L. R., Jamieson, D. J., Powers, A. M. & Honein, M. A. Zika virus. N. Engl. J. Med. 374, 1552–1563 (2016).
Dick, G., Kitchen, S. & Haddow, A. Zika virus (I). Isolations and serological specificity. Trans. R. Soc. Trop. Med. Hyg. 46, 509–520 (1952).
Armstrong, P. et al. Zika virus response epidemiology and laboratory team. Travel-associated Zika virus disease cases among US residents—United States, January 2015–February 2016. Morb. Mortal. Wkly. Rep. 65, 286–289 (2016).
Bachiller-Luque, P. et al. First case of imported Zika virus infection in Spain. Enferm. Infecc. Microbiol. Clin. 34, 243–246 (2016).
Li, J. et al. Zika virus in a traveler returning to China from Caracas, Venezuela, February 2016. Emerg. Infect. Dis. 22, 1133–1136 (2016).
Perkasa, A. et al. Isolation of Zika virus from febrile patient. Indonesia. Emerg. Infect. Dis. 22, 924–925 (2016).
Thomas, D. L. Local transmission of Zika virus—Puerto Rico, November 23, 2015–January 28, 2016. Morb. Mortal. Wkly. Rep. 65, 154–158 (2016).
World Health Organization. Emergencies - Zika virus situation reports. WHO http://www.who.int/emergencies/zika-virus/situation-report/en/ (2018).
World Health Organization. Zika virus (ZIKV) classification table data as of 20 June 2017. WHO http://apps.who.int/iris/bitstream/10665/255767/1/zika-classification-20June17-eng.pdf?ua=1 (2017).
Zammarchi, L. et al. Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications. J. Clin. Virol. 63, 32–35 (2015).
Cao-Lormeau, V. M. et al. Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 387, 1531–1539 (2016).
Kuno, G., Chang, G. J. J., Tsuchiya, K. R., Karabatsos, N. & Cropp, C. B. Phylogeny of the genus Flavivirus. J. Virol. 72, 73–83 (1998).
Chan, J. F., Choi, G. K., Yip, C. C., Cheng, V. C. & Yuen, K. Y. Zika fever and congenital Zika syndrome: an unexpected emerging arboviral disease. J. Infect. 72, 507–524 (2016).
Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).
Mlakar, J. et al. Zika virus associated with microcephaly. N. Engl. J. Med. 374, 951–958 (2016).
Duffy, M. R. et al. Zika virus outbreak on Yap Island, federated states of Micronesia. N. Engl. J. Med. 360, 2536–2543 (2009).
Kraemer, M. U. et al. The global distribution of the arbovirus vectors Aedes aegypti and A. albopictus. eLife 4, 1–18 (2015).
Gardner, L. M., Chen, N. & Sarkar, S. Global risk of Zika virus depends critically on vector status of Aedes albopictus. Lancet Infect. Dis. 16, 522–523 (2016).
McCarthy, M. Vectors for Zika virus may spread further than was previously thought, CDC reports. BMJ 353, 1 (2016).
Centers for Disease Control and Prevention. Guidance for U.S. laboratories testing for Zika virus infection. CDC https://www.cdc.gov/zika/laboratories/lab-guidance.html (updated July 24 2017).
Arsuaga, M., Bujalance, S. G., Díaz-Menéndez, M., Vázquez, A. & Arribas, J. R. Probable sexual transmission of Zika virus from a vasectomised man. Lancet Infect. Dis. 16, 1107 (2016).
Davidson, A. Suspected female-to-male sexual transmission of Zika virus—New York City, 2016. Morb. Mortal. Wkly. Rep. 65, 716–717 (2016).
Deckard, D. T. Male-to-male sexual transmission of Zika virus—Texas, January 2016. Morb. Mortal. Wkly. Rep. 65, 372–374 (2016).
D’Ortenzio, E. et al. Evidence of sexual transmission of Zika virus. N. Engl. J. Med. 374, 2195–2198 (2016).
Foy, B. D. et al. Probable non–vector-borne transmission of Zika virus, CO, USA. Emerg. Infect. Dis. 17, 880–882 (2011).
Hills, S. L. Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission—continental United States, 2016. Morb. Mortal. Wkly. Rep. 65, 215–216 (2016).
Brooks, R. B. Likely sexual transmission of Zika virus from a man with no symptoms of infection—Maryland, 2016. Morb. Mortal. Wkly. Rep. 65, 915–916 (2016).
Fréour, T. et al. Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016. Euro. Surveill. 21, 30254 (2016).
Turmel, J. M. et al. Late sexual transmission of Zika virus related to persistence in the semen. Lancet 387, 2501 (2016).
Venturi, G. et al. An autochthonous case of Zika due to possible sexual transmission, Florence, Italy, 2014. Euro. Surveill. 21, 30148 (2016).
Frank, C. et al. Sexual transmission of Zika virus in Germany, April 2016. Euro. Surveill. 21, 30252 (2016).
Russell, K. et al. Male-to-female sexual transmission of Zika virus—United States, January–April 2016. Clin. Infect. Dis. 64, 211–213 (2016).
Barzon, L. et al. Virus and antibody dynamics in travelers with acute zika virus infection. Clin. Infect. Dis. 66, 1173–1180 (2017).
Musso, D. et al. Potential sexual transmission of Zika virus. Emerg. Infect. Dis. 21, 359–361 (2015).
Nicastri, E. et al. Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016. Euro. Surveill. 21, 30314 (2016).
Reusken, C. et al. Longitudinal follow-up of Zika virus RNA in semen of a traveller returning from Barbados to the Netherlands with Zika virus disease, March 2016. Euro. Surveill. 21, 30251 (2016).
Mansuy, J. M. et al. Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen. Lancet Infect. Dis. 16, 405 (2016).
Paz-Bailey, G. et al. Persistence of Zika virus in body fluids—preliminary report. N. Engl. J. Med. 379, 1234–1243 (2017).
Mansuy, J. M. et al. Zika virus in semen and spermatozoa. Lancet Infect. Dis. 16, 1106–1107 (2016).
Barzon, L. et al. Infection dynamics in a traveller with persistent shedding of Zika virus RNA in semen for six months after returning from Haiti to Italy, January 2016. Euro. Surveill. 21, 30316 (2016).
Atkinson, B. et al. Detection of Zika virus in semen. Emerg. Infect. Dis. 22, 940 (2016).
Harrower, J. et al. Sexual transmission of Zika virus and persistence in semen, New Zealand, 2016. Emerg. Infect. Dis. 22, 1855–1857 (2016).
Mansuy, J. M. et al. Zika virus in semen of a patient returning from a non-epidemic area. Lancet Infect. Dis. 16, 894–895 (2016).
García-Bujalance, S. et al. Persistence and infectivity of Zika virus in semen after returning from endemic areas: report of 5 cases. J. Clin. Virol. 96, 110–115 (2017).
Huits, R. et al. Kinetics of Zika virus persistence in semen. Bull. World Health Organ. 6, 1–12 (2016).
Souto, I. O. et al. Persistence of Zika virus in semen 93 days after the onset of symptoms. Enferm. Infecc. Microbiol. Clin. 36, 21–23 (2016).
Huits, R. et al. Zika virus in semen: a prospective cohort study of symptomatic travellers returning to Belgium. Bull. World Health Organ. 95, 802–809 (2017).
Froeschl, G. et al. Long-term kinetics of Zika virus RNA and antibodies in body fluids of a vasectomized traveller returning from Martinique: a case report. BMC Infect. Dis. 17, 55 (2017).
Atkinson, B. et al. Complete genome sequence of Zika virus isolated from semen. Genome Announc. 4, e01116–16 (2016).
Sánchez-Montalvá, A. et al. Zika virus dynamics in body fluids and risk of sexual transmission in a non-endemic area. Trop. Med. Int. Health 23, 92–100 (2018).
Torres, J. R., Martínez, N. & Moros, Z. Microhematospermia in acute Zika virus infection. Int. J. Infect. Dis. 51, 127 (2016).
Joguet, G. et al. Effect of acute Zika virus infection on sperm and virus clearance in body fluids: a prospective observational study. Lancet Infect. Dis. 17, 1200–1208 (2017).
Biava, M. et al. Persistence of ZIKV-RNA in the cellular fraction of semen is accompanied by a surrogate-marker of viral replication. Diagnostic implications for sexual transmission. New Microbiol. 40, 30–33 (2017).
Gaskell, K. M., Houlihan, C., Nastouli, E. & Checkley, A. M. Persistent Zika virus detection in semen in a traveler returning to the United Kingdom from Brazil, 2016. Emerg. Infect. Dis. 23, 137–139 (2017).
Mead, P. S. et al. Zika virus shedding in semen of symptomatic infected men. N. Engl. J. Med. 378, 1377–1385 (2018).
Epelboin, S. et al. Zika virus and reproduction: facts, questions and current management. Hum. Reprod. Update 23, 629–645 (2017).
Rasmussen, S. A., Jamieson, D. J., Honein, M. A. & Petersen, L. R. Zika virus and birth defects—reviewing the evidence for causality. N. Engl. J. Med. 374, 1981–1987 (2016).
Dos Santos, T. et al. Zika virus and the Guillain–Barré syndrome—case series from seven countries. N. Engl. J. Med. 375, 1598–1601 (2016).
Aubry, M. et al. Zika virus seroprevalence, French Polynesia, 2014–2015. Emerg. Infect. Dis. 23, 669–672 (2017).
Chakhtoura, N., Hazra, R. & Spong, C. Y. Zika virus: a public health perspective. Curr. Opin. Obstet. Gynecol. 30, 116–122 (2018).
Stefanovic, K. B., Gregg, P. C. & Soung, M. Evaluation and treatment of hematospermia. Am. Fam. Physician 80, 1421–1427 (2009).
Atkinson, B. et al. Presence and persistence of Zika virus RNA in semen, United Kingdom, 2016. Emerg. Infect. Dis. 23, 611–615 (2017).
Bagasra, O. et al. Cellular targets and receptor of sexual transmission of Zika virus. Appl. Immunohistochem. Mol. Morphol. 25, 679–686 (2017).
Lemke, G. Biology of the TAM receptors. Cold Spring Harb. Perspect. Biol. 5, 1–17 (2013).
Breton, S. & Stewart, D. T. Atypical mitochondrial inheritance patterns in eukaryotes. Genome 58, 423–431 (2015).
Bagasra, O. et al. Detection of HIV-1 proviral DNA in sperm from HIV-1-infected men. AIDS 8, 1669–1674 (1994).
Shimojima, M. et al. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J. Virol. 80, 10109–10116 (2006).
Shimojima, M., Ikeda, Y. & Kawaoka, Y. The mechanism of Axl-mediated Ebola virus infection. J. Infect. Dis. 196, S259–S263 (2007).
Meertens, L. et al. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe 12, 544–557 (2012).
Charrel, R. N. et al. Background review for diagnostic test development for Zika virus infection. Bull. World Health Organ. 94, 574–584 (2016).
World Health Organization. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. WHO http://www.who.int/en/news-room/detail/01-02-2016-who-director-general-summarizes-the-outcome-of-the-emergency-committee-regarding-clusters-of-microcephaly-and-guillain-barr%C3%A9-syndrome (2016).
Li, R. et al. Zika virus infections, a review. Radiol. Infect. Dis. 4, 88–93 (2017).
da Cruz, T. E. et al. Prolonged detection of Zika Virus RNA in vaginal and vndocervical samples from a Brazilian woman, 2018. Am. J. Trop. Med. Hyg. https://doi.org/10.4269/ajtmh.18-0623 (2018).
Morrison, T. E. & Diamond, M. S. Animal models of Zika virus infection, pathogenesis, and immunity. J. Virol. 91, e00009–17 (2017).
Osuna, C. E. et al. Zika viral dynamics and shedding in rhesus and cynomolgus macaques. Nat. Med. 22, 1448–1455 (2016).
Koide, F. et al. Development of a Zika virus infection model in cynomolgus macaques. Front. Microbiol. 7, 2028 (2016).
Hirsch, A. J. et al. Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. PLOS Pathog. 13, e1006219 (2017).
Dudley, D. M. et al. A rhesus macaque model of Asian-lineage Zika virus infection. Nat. Commun. 7, 12204 (2016).
Spearman, P. Current progress in the development of HIV vaccines. Curr. Pharm. Des. 12, 1147–1167 (2006).
Antony, J. M. & MacDonald, K. S. A critical analysis of the cynomolgus macaque, Macaca fascicularis, as a model to test HIV-1/SIV vaccine efficacy. Vaccine 33, 3073–3083 (2015).
Andrade, M. C. R. et al. Biologic data of Macaca mulatta, Macaca fascicularis, and Saimiri sciureus used for research at the fiocruz primate center. Mem. Inst. Oswaldo Cruz 99, 584–589 (2004).
Govero, J. et al. Zika virus infection damages the testes in mice. Nature 540, 438–442 (2016).
Ma, W. et al. Zika virus causes testis damage and leads to male infertility in mice. Cell 167, 1511–1524 (2016).
Winkler, C. W. et al. Adaptive immune responses to Zika virus are important for controlling virus infection and preventing infection in brain and testes. J. Immunol. 198, 3526–3535 (2017).
Uraki, R. et al. Zika virus causes testicular atrophy. Sci. Adv. 3, e1602899 (2017).
Sheng, Z. Y. et al. Sertoli cells are susceptible to ZIKV infection in mouse testis. Front. Cell. Infect. Microbiol. 7, 272 (2017).
Uraki, R. et al. Fetal growth restriction caused by sexual transmission of Zika virus in mice. J. Infect. Dis. 215, 1720–1724 (2017).
Kawiecki, A. B. et al. Tissue tropisms, infection kinetics, histologic lesions, and antibody response of the MR766 strain of Zika virus in a murine model. Virol. J. 14, 82 (2017).
Duggal, N. K. et al. Frequent Zika virus sexual transmission and prolonged viral RNA shedding in an immunodeficient mouse model. Cell Rep. 18, 1751–1760 (2017).
Chan, J. F. W. et al. Zika virus infection in dexamethasone-immunosuppressed mice demonstrating disseminated infection with multi-organ involvement including orchitis effectively treated by recombinant type I interferons. EBioMedicine 14, 112–122 (2016).
Siddharthan, V. et al. Zika virus infection of adult and fetal STAT2 knock-out hamsters. Virology 507, 89–95 (2017).
Grant, A. et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 882–890 (2016).
Lazear, H. M. et al. A mouse model of Zika virus pathogenesis. Cell Host Microbe 19, 720–730 (2016).
Griffin, B. D. et al. DNA vaccination protects mice against Zika virus-induced damage to the testes. Nat. Commun. 8, 15743 (2017).
Xu, K. et al. Recombinant chimpanzee adenovirus vaccine AdC7-M/E protects against Zika Virus infection and testis damage. J. Virol. 92, e01722–17 (2018).
Tang, H. et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18, 587–590 (2016).
Zmurko, J. et al. The viral polymerase inhibitor 7-deaza-2′-C-methyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. PLOS Negl. Trop. Dis. 10, e0004695 (2016).
Chen, J. et al. Zika virus infects renal proximal tubular epithelial cells with prolonged persistency and cytopathic effects. Emerg. Microbes Infect. 6, e77 (2017).
Jang, H. C. et al. First imported case of Zika virus infection into Korea. J. Kor. Med. Sci. 31, 1173–1177 (2016).
Percivalle, E., Zavattoni, M., Fausto, F. & Rovida, F. Zika virus isolation from semen. New Microbiol. 40, 197–198 (2017).
Matheron, S. et al. Long-lasting persistence of Zika virus in semen. Clin. Infect. Dis. 63, 1264–1264 (2016).
Spencer, J. L. et al. Replication of Zika virus in human prostate cells: a potential source of sexually transmitted virus. J. Infect. Dis. 217, 538–547 (2018).
Kim, W. et al. RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc. Natl Acad. Sci. USA 111, 16389–16394 (2014).
Kumar, A. et al. Human Sertoli cells support high levels of Zika virus replication and persistence. Sci. Rep. 8, 5477 (2018).
Takashima, S. et al. Functional differences between GDNF-dependent and FGF2-dependent mouse spermatogonial stem cell self-renewal. Stem Cell Rep. 4, 489–502 (2015).
Dym, M. & Fawcett, D. W. The blood-testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium. Biol. Reprod. 3, 308–326 (1970).
Dym, M. The fine structure of the monkey (Macaca) Sertoli cell and its role in maintaining the blood-testis barrier. Anat. Rec. 175, 639–656 (1973).
Kaur, G., Thompson, L. A. & Dufour, J. M. Sertoli cells - Immunological sentinels of spermatogenesis. Semin. Cell Dev. Biol. 30, 36–44 (2014).
Sharpe, R. M., McKinnell, C., Kivlin, C. & Fisher, J. S. Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction 125, 769–784 (2003).
Chui, K. et al. Characterization and functionality of proliferative human Sertoli cells. Cell Transplant. 20, 619–635 (2011).
Amann, R. P. The cycle of the seminiferous epithelium in humans: a need to revisit? J. Androl. 29, 469–487 (2008).
World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen (WHO, 2010).
Robert, M. & Gagnon, C. Sperm motility inhibitor from human seminal plasma: association with semen coagulum. Hum. Reprod. 10, 2192–2197 (1995).
Comhaire, F. H., Vermeulen, L. & Pieters, O. Study of the accuracy of physical and biochemical markers in semen to detect infectious dysfunction of the accessory sex glands. J. Androl. 10, 50–53 (1989).
Cordeiro, C. N., Bano, R., Cross, C. I. W. & Segars, J. H. Zika virus and assisted reproduction. Curr. Opin. Obstet. Gynecol. 29, 175–179 (2017).
Lee, W. T. et al. Development of Zika virus serologic testing strategies in New York state. J. Clin. Microbiol. 56, e01591–17 (2017).
Musso, D. et al. Detection of Zika virus RNA in semen of asymptomatic blood donors. Clin. Microbiol. Infect. 23, e1001–e1003 (2017).
American Society for Reproductive Medicine. Guidance for providers caring for women and men of reproductive age with possible Zika virus exposure. asrm https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/practice-guidelines/for-non-members/guidance_for_providers_zika_virus_exposure.pdf (2018).
Washington, C. I. et al. Keeping the Zika virus out of the assisted reproductive technology laboratory. Semin. Reprod. Med. 34, 293–298 (2016).
Food and Drug Administration. Donor screening recommendations to reduce the risk of transmission of Zika virus by human cells, tissues, and cellular and tissue-based products. FDA https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/tissue/ucm488582.pdf (2016).
This work was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível superior (CAPES), Brazilian Government.
The authors performed an extensive PubMed, MEDLINE, Web of Science and Scopus Scholar search for full-text papers and abstracts published in English, with no restrictions regarding to the initial date of publication up to April 2018. Search terms used were ‘Zika virus’ and ‘Zika virus infection’ plus ‘male infertility’, ‘fertility’, ‘infertility’, ‘semen’, ‘spermatozoa’, ‘testis’, ‘epididymis’, ‘seminal vesicles’, ‘prostate’, ‘seminiferous tubules’, ‘orchitis’, ‘prostatitis’, ‘urethritis’, ‘vasectomy’, ‘Sertoli cells’, ‘spermatogonia’, ‘Leydig cells’, ‘spermatogenesis’, ‘haematospermia’, ‘oligospermia’, ‘azoospermia’, ‘sperm motility’, ‘semen analysis’ and ‘cell culture techniques’. In addition, the reference lists of the selected papers were searched for additional relevant publications. Epidemiology bulletins from the US Centers for Disease Control and Prevention (CDC) were also included.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Kurscheidt, F.A., Mesquita, C.S.S., Damke, G.M.Z.F. et al. Persistence and clinical relevance of Zika virus in the male genital tract. Nat Rev Urol 16, 211–230 (2019). https://doi.org/10.1038/s41585-019-0149-7