- Open Access
Seminal shedding of human herpesviruses
Virology Journalvolume 10, Article number: 226 (2013)
Most of the human herpesviruses can be found in semen, although the reported prevalence varies considerably between individual studies. The frequent presence of herpesvirus in semen raises the question whether sexual transmission of the virus could have an impact on human reproduction. Only few studies have associated seminal shedding of herpesviruses with impaired sperm quality, reduced fertility, or reduced chances of pregnancy, whereas most studies fail to find an association. Taken together, no firm evidence is so far linking the presence of herpesviruses in semen to impaired human reproduction.
It is well established that many pathogens may cause sexually transmitted diseases (STD). Examples include bacterial infections with Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, which may impair fertility or cause severe congenital disorders. Also viral infections with herpes simplex virus type 2 (HSV-2), causing genital herpes, or human immunodeficiency virus (HIV), which untreated may lead to AIDS, are significant health care issues. It is generally believed that transmission of pathogens causing STD occurs through direct contact between mucous membranes, however accumulating reports have indicated that several bacteria [1, 2] and viruses, including HIV , human papillomavirus (HPV) , hepatitis B virus , hepatitis C virus , Ebola virus , adenovirus , and various human herpesviruses (HHV) are present in semen. This suggests that semen may also be an important transmission route, although its precise role can be difficult to establish. This review will focus on herpesviruses in semen and their potential significance for human reproduction.
The family of Herpesviridae consists of nine structurally similar, large, enveloped DNA viruses, which all share the ability to persist latently in the host cell and give rise to recurrent infections. The HHV have been divided into three subfamilies (α, β, and γ) based on both virological and biological properties, including the type of primary target cells and the site of latency. No studies today have examined the individual prevalence of all nine HHV in semen. The individual studies are summarized in Table 1 (α- and γ-HHV) and Table 2 (β-HHV).
Herpes simplex virus-1 and -2
HSV-1 and -2 are neurotropic α-HHVs. HSV-1 is primarily associated with oral transmission and recurrent oral lesions, whereas HSV-2 is the major cause of genital herpes, although both viruses are capable of infecting any region of the body. Primary or recurrent infections can occur either symptomatically or asymptomatically. The seroprevalence of HSV-1 and HSV-2 increases with age in both Europe and the USA, reaching a plateau around age 40 with a prevalence of approximately 70% for HSV-1 and 40-60% for HSV-2 in “high-risk” populations and 20-35% for HSV-2 in “low-risk” populations . The prevalence of HSV-1 is roughly similar in Europe and the USA, whereas the prevalence of HSV-2 is considerable higher in the USA . Frequently, studies have not discriminated between HSV-1 and -2; in these cases, we refer to HSV-1/2. HSV-1/2 is sexually transmissible , and mother-to-child transmission occurs in 1:1,400-30,000 births, occasionally causing a life threatening generalized infection in the new-born child .
The prevalence of HSV-1/2 in semen varies substantially between different studies (Table 1). More than half of the studies have reported frequencies of less than 4% in both fertile and infertile men, but particularly studies from Greece  and Russia  find, using nested PCR and in situ hybridization, respectively, that almost half of the semen samples from fertility-clinic attendants contain HSV-1/2. Moreover, also using nested PCR a study from Japan  found HSV-1/2 in semen from 24% of fertility-clinic attendants, but none in semen from their fathers. Whether these significant variations in prevalence are due to methodological differences, or reflect a true variation between study populations may require additional analyses to solve. Out of four studies, three found the parameters in routine sperm analyses to be normal in sperm from HSV-1/2 positive men or in sperm exposed to HSV-1/2 in vitro [11, 23, 44]. The fourth study found that the presence of HSV-1/2 was associated with low sperm count and poor motility . Indeed, HSV-2 isolated from the testis of a dead man has been reported infectious , and one case of HSV-2 transmission through donor semen to a recipient, who subsequently acquired a primary infection, has also been reported . Moreover, Bocharova et al.  have reported that HSV-2 can be internalized into the heads of morphological normal and motile sperm, suggesting a potential effect of HSV on pregnancy and outcome. Other groups have not yet confirmed this interesting observation.
Taken together, the data so far do not suggest that HSV-1/2 is involved in impaired fertility. Besides from a study of transmission by insemination, the mucosa-associated HSV-1/2 transmission makes it difficult to estimate the risk of HSV-1/2 transmission in semen per se. If an association with sperm heads is a general feature of HSV-2, this might have implications for infection of the endometrium, and warrants additional investigations to clarify.
Varicella-zoster virus (VZV) is an α-herpesvirus infecting most unvaccinated people during early childhood. Primary infection manifests itself as a usually benign childhood disease, varicella (chicken pox), whereas reactivation results in zoster (shingles).
Only few studies have investigated the potential presence of VZV in semen. Except for one study from Greece , there is agreement that VZV is neither present in semen from fertility-clinic attendants (Germany) , nor from men of couples undergoing IVF treatment (Spain) , or from healthy sperm donors (Denmark) . Taken together, the evidence indicates that VZV is not present in semen, perhaps reflecting the infrequency of VZV reactivation occurring from the ganglia rather than immune cells.
Epstein-Barr virus (EBV) is a γ-herpesvirus that is primarily B-lymphotropic, although it may also infect and replicate in epithelia cells in vivo. The age of acquisition of EBV (measured by antibodies) varies in different geographic areas. When acquired in early childhood, the infection is usually asymptomatic, whereas primary infection during puberty may cause infectious mononucleosis. The transmission during puberty involves saliva with high-titered EBV, but might also be transmitted through genital secretions, probably through cell-associated EBV [27, 46]. EBV can be present in cervical cells  and can be transmitted from mother-to-child in approximately 3% of EBV PCR positive mothers . It has not been reported whether the presence of EBV might impair endometrium receptivity.
An association with leukocytospermia and an increased mean sperm count have been reported in EBV-positive semen samples [11, 23], whereas others do not find an impact on sperm count or motility . Anyhow, it is not known whether the prevalence of EBV in semen of infertile and fertile men differs. Separate studies on sperm donors and fertility-clinic attendants demonstrate variations in prevalence between studies from 0.4 to 45% (Table 1). A recent study found significantly increased prevalence of EBV in semen and blood of HIV-infected individuals. Even in cases with no detectable EBV in the blood, EBV was present in semen suggesting compartmentalized reactivation .
In conclusion, it has not been convincingly demonstrated that EBV in semen impairs sperm function. Estimates indicate that sexual transmission is a minor route of infection, but the demonstration of EBV in cervical cells may warrant further investigation of a potential role of EBV during reproduction.
Human herpesvirus 8
HHV-8, also known as Kaposi’s Sarcoma-Associated Herpesvirus or KSAV, is a γ-herpesvirus that primarily, but not exclusively, infects B cells. Infection with HHV-8 is predominantly seen in certain geographic regions in Africa and South America, but this is usually among older adults. The infection is also observed in immunosuppressed individuals, but is rare in healthy individuals from North America, North Europe and Asia. Not surprisingly, most studies have therefore failed to detect HHV-8 in sperm from healthy donors or fertility-clinic attendants (Kaspersen et al., unpublished observation and [11, 19]). In contrast, Bagasra et al. reported HHV-8 in 2 of 45 semen samples from HIV-negative men, but further demographic information on these men was not provided. However, HHV-8 was found in semen samples from 64 of 73 (88%) HIV-positive homosexual men. HHV-8 in semen was present in both sperm and mononuclear cells . The prevalence of HHV-8 in previous studies have ranged from 0 to more than 90%, which may reflect methodological differences (including sensitivity and PCR contaminations), differences in HIV status, or geographic and population-based differences (see ref , and references herein).
HHV-5 or human cytomegalovirus (HCMV) is a β-herpesvirus to which seroconversion occurs throughout life. Infection by HCMV is often asymptomatic, but clinically important infections occur in immunocompromised individuals or in pregnant women that subsequently may give birth to a child with congenital infection. Severe congenital HCMV infection is associated with growth retardation, mental retardation, deafness, microcephaly, hepatosplenomegaly, chorioretinitis, calcification, and neurologic impairment (for review, see Revello and Gerna ).
It has been almost four decades since HCMV was first reported in semen from American men of various populations . Since then, numerous reports on identification of HCMV in semen from differently defined population groups have accumulated. The majority of these studies report a prevalence of approximately 6% in men from Germany, North America, France, Africa, Greece, Denmark, Australia, and Russia (Table 1). In contrast, several studies on semen of fertility-clinic attendants from China, Taiwan, Spain, and Greece, have reported high prevalences of HCMV between 21.6% to 56.9% [14, 22, 23, 38, 40]. This could possibly be explained by geographic variation, however another study from Greece, also of semen from fertility-clinic attendants, found HCMV in only 7.1% . Both Greek studies used PCR for HCMV DNA detection; the study that detected the lower frequency even used nested PCR . Shedding of HCMV in semen is also relatively high in homosexual men [24, 39]. Howard et al. found shedding of HCMV in 20 out of 24 HIV-positive, homosexual men (83.3%), but only in 4 out of 115 healthy donors (3.5%) .
Although one case of hematospermia has been associated with HCMV shedding , most groups have found the sperm parameters to be unaffected by HCMV [8, 11, 17, 23, 31, 32, 40, 44], and two studies that directly compare the prevalence of HCMV in semen from fertile and infertile men find similar frequencies within the two groups [37, 50].
HCMV in semen may be infectious [20, 24, 39], and HCMV has also been isolated from human endometrial cells , suggesting a possible mechanism of direct infection of the endometrial cells by HCMV carried by sperm. Moreover, productive HCMV infection can be obtained in human endometrial stroma cells . Since a primary HCMV infection is associated with an increased risk for early abortion [54, 55] and congenital defects in the fetus in general , HCMV in semen remains a potential risk of viral transmission, even though this may be an infrequent route of infection.
Whether HCMV directly impairs sperm fertility has been investigated by Eggert-Kruse and coworkers . From subfertile couples, semen from 170 males and endocervical material from 156 females were screened for the presence of HCMV by nested PCR. The presence of HCMV was not concordant between couples, emphasizing that sexual transmission of HCMV is not a frequent route of infection. Furthermore, no significant correlations between HCMV and semen quality or between cervical HCMV-infection and mucus quality or female infertility factor were seen.
In conclusion, sexual transmission of HCMV is rare, but semen may contain infectious virus with the potential of initiating a primary infection. However, there is no evidence that HCMV in semen impairs fertility . Longitudinal studies on pregnancy outcome in HCMV-positive versus HCMV-negative patients are, however, lacking.
Human herpesvirus 6A/B
Closely related to HCMV, the β-herpesviruses HHV-6A and HHV-6B are frequently examined by methods that do not allow a distinction between the two viruses. Infection usually occurs in the first years of life giving rise to the childhood disease exanthem subitum, and most adults in the Western world are seropositive. HHV-6B has tropism for mononuclear cells, primarily T cells, but is usually found in saliva, which is thought to be the major route of transmission.
Only few reports are available on the prevalence of HHV-6A/B in human semen. Bezold et al. found the prevalence to be 4.0% in a German population of infertility patients  and 3.7% in a population of American infertility patients . Chen et al. found HHV-6A/B in 2.0% of infertility patients from China , whereas Michou et al. detected HHV-6A/B in 8.2% of 109 men from couples undergoing IVF treatment in Spain . A slightly higher prevalence of 13.5% was seen by Kaspersen et al. in semen from Danish sperm donors  (Table 2), suggesting that the prevalence of HHV-6A/B is not increased among patients attending a fertility clinic. A remarkably high prevalence of 66.8% among men attending a fertility clinic on Crete has been reported by Neofytou et al. using nested PCR . The discrepancies in HHV-6A/B prevalence are most likely not due to geographic or population-based differences, since HHV-6A/B appears to be present in all the populations. The most likely explanations are therefore that the nested PCR procedure of Neofytou et al. might be more sensitive or was contaminated. Nonetheless, it is clear that HHV-6A/B does not directly affect sperm parameters [11, 23]. Interestingly, HHV-6A/B is associated with the acrosome of the sperm , but it is not known whether this provide a mechanism for infecting the endometrium.
The binding of HHV-6B to the acrosome  suggests that HHV-6B may be transmitted to the uterus by the sperm, but at the same time this may argue against infection of the oocyte during normal fertilization, since the acrosome is dissolved prior to the sperm enters the egg. Nevertheless, HHV-6A/B integrates chromosomally at a frequency of 0.8% , and it remains unknown how this integration might happen. Thus, it is expected that PCR-based detection should identify approximately 1% of semen samples simply due to chromosomal integration of either HHV-6A or HHV-6B.
In conclusion, there is no evidence so far to indicate that HHV-6A/B affects sperm function or other aspects of human reproduction, although a potential role of HHV-6A/B on the endometrium has not been resolved yet.
Human herpesvirus 7
HHV-7 is a β-herpesvirus closely related to HHV-6A and HHV-6B. HHV-7 is usually acquired prior to age 5, and seroprevalence in adults reaches 96% . Infection by HHV-7 is either asymptomatic or causes exanthem subitum.
Similar to HHV-6A/B, the prevalence of HHV-7 in semen is also based on only few publications. The prevalence in semen from European sperm donors or men attending a fertility clinic is similar and within the range of 0.4 to 6.0% (Table 2). HIV-positive men have a slightly higher prevalence, which could be explained by reactivation of HHV-7 by HIV, although the increase in HHV-7 prevalence is not nearly at the same level of that seen for HCMV . HHV-7 has been detected in a small percentage of analyzed cervical swaps  and in one out of eleven analyzed placental biopsy samples , but any association to human reproduction has not been reported. Effects of HHV-7 on sperm parameters have not been evaluated.
In conclusion, there is no evidence to link HHV-7 with human reproduction. It cannot be excluded that HHV-7 can be transmitted sexually, but the significance of this route, if any, is unknown at present.
HSV seroprevalence has been reported higher for a population of female fertility-clinic attendants compared to a population of pregnant women  and high HHV-6A/B antibody titers has been associated with a reduced chance of pregnancy . Nevertheless, the collective set of data does not indicate an association between herpesviruses in semen and reduced fertility.
However, if sperm-associated herpesvirus is transmissible to the female cervix or perhaps even to the endometrium, as has been reported for HSV-2 , the consequences may be more difficult to estimate. For instance, the leukemia inhibitory factor (LIF) cytokine is essential for blastocyst implantation. Mouse LIF-null uteri are unreceptive, yet LIF-deleted blastocysts are unaffectedly implanted into normally functioning uteri . Unexplained female infertility is not associated with mutations in the LIF gene . Hu et al.  have shown that the production of LIF is partially regulated by p53 and that p53-null mice blastocyst implantation rate is significantly reduced. Herpesviruses such as HSV-1, HCMV, and HHV-6B have the ability to inactivate p53. Thus, implantation of the blastocyst could hypothetically be negatively influenced by viral infection of uterus tissue. Although the presence of HHV-6B in cells of the endometrium has not yet been investigated, it is possible that local infection or reactivation of these herpesviruses occurs and that viral activity in cells involved in endometrium receptivity would have a negative effect on human fertility.
Nevertheless, no evidence suggests so far that herpesvirus infection has a negative influence on reproduction. Indeed pre-pregnancy seropositivity to several viruses protects against primary infection during pregnancy, decreasing the risk for pregnancy complications such as preeclampsia . Perhaps maternal infection by certain (herpes) viruses even protects against other more harmful infections.
The source of herpesviruses in semen has also yet to be determined. It is commonly known that mumps virus has the potential to infect the testis. Herpesviruses might share this ability to infect testis tissue. Indeed, EBV and HSV-1 and -2 have been isolated from human testis, and murine CMV (MCMV) from mouse testis. Additionally, HSV-2 and HCMV have been identified in prostate tissue, but the effect of herpesvirus infection at these sites is controversial .
Because of the risks of HCMV-mediated congenital defects, the interest for HCMV-screening on donor semen is increasing. Yet, it is not clear whether HCMV constitutes a threat to the semen recipient, but since HCMV isolated from semen is infectious [20, 24, 39], and since purification of HCMV positive semen does not efficiently eliminate the virus , the potential risk of HCMV transmission during assisted reproductive techniques (ART) cannot be ignored. Serology does not predict the presence of HCMV in semen or cervix , therefore screening of donor semen for HCMV DNA is necessary to prevent the use of HCMV-contaminated sperm in ART. Unfortunately, this would be costly, because shedding of herpesviruses fluctuates, necessitating screening of all semen samples rather than occasional checks .
Acquired immunodeficiency syndrome
Artificial reproductive technique
Herpes simplex virus
Kaposi’s sarcoma-associated herpesvirus
Polymerase chain reaction
Sexually transmitted disease
Friberg J, Confino E, Suarez M, Gleicher N: Chlamydia trachomatis attached to spermatozoa recovered from the peritoneal cavity of patients with salpingitis. J Reprod Med 1987, 32: 120-122.
Fourie J, Loskutoff N, Huyser C: Elimination of bacteria from human semen during sperm preparation using density gradient centrifugation with a novel tube insert. Andrologia 2012,44(Suppl 1):513-517.
Baccetti B, Benedetto A, Burrini AG, Collodel G, Elia C, et al.: HIV particles detected in spermatozoa of patients with AIDS. J Submicrosc Cytol Pathol 1991, 23: 339-345.
Kaspersen MD, Larsen PB, Ingerslev HJ, Fedder J, Petersen GB, et al.: Identification of multiple HPV types on spermatozoa from human sperm donors. PLoS One 2011, 6: e18095. 10.1371/journal.pone.0018095
Hadchouel M, Scotto J, Huret JL, Molinie C, Villa E, et al.: Presence of HBV DNA in spermatozoa: a possible vertical transmission of HBV via the germ line. J Med Virol 1985, 16: 61-66. 10.1002/jmv.1890160109
Briat A, Dulioust E, Galimand J, Fontaine H, Chaix ML, et al.: Hepatitis C virus in the semen of men coinfected with HIV-1: prevalence and origin. AIDS 2005, 19: 1827-1835. 10.1097/01.aids.0000189847.98569.2d
Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, et al.: Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis 2007,196(Suppl 2):S142-S147.
Erles K, Rohde V, Thaele M, Roth S, Edler L, et al.: DNA of adeno-associated virus (AAV) in testicular tissue and in abnormal semen samples. Hum Reprod 2001, 16: 2333-2337.
Aynaud O, Poveda JD, Huynh B, Guillemotonia A, Barrasso R: Frequency of herpes simplex virus, cytomegalovirus and human papillomavirus DNA in semen. Int J STD AIDS 2002, 13: 547-550. 10.1258/095646202760159666
Bagasra O, Patel D, Bobroski L, Abbasi JA, Bagasra AU, et al.: Localization of human herpesvirus type 8 in human sperms by in situ PCR. J Mol Histol 2005, 36: 401-412.
Bezold G, Schuster-Grusser A, Lange M, Gall H, Wolff H, et al.: Prevalence of human herpesvirus types1–8in the semen of infertility patients and correlation with semen parameters. Fertil Steril 2001, 76: 416-418. 10.1016/S0015-0282(01)01920-3
Bezold G, Politch JA, Kiviat NB, Kuypers JM, Wolff H, et al.: Prevalence of sexually transmissible pathogens in semen from asymptomatic male infertility patients with and without leukocytospermia. Fertil Steril 2007, 87: 1087-1097. 10.1016/j.fertnstert.2006.08.109
Bocharova EN, Zavalishina LE, Bragina EE, Klimova RR, Gusak YK, et al.: Detection of herpes simplex virus genomic DNA in spermatozoa of patients with fertility disorders by in situ hybridization. Dokl Biol Sci 2007, 412: 82-86. 10.1134/S0012496607010279
Chen M, Cai LY, Kanno N, Kato T, Lu J, et al.: Detection of human herpesviruses (HHVs) in semen of human male infertile patients. J Reprod Dev 2013. in press
el Borai N, Inoue M, Lefevre C, Naumova EN, Sato B, et al.: Detection of herpes simplex DNA in semen and menstrual blood of individuals attending an infertility clinic. J Obstet Gynaecol Res 1997, 23: 17-24. 10.1111/j.1447-0756.1997.tb00799.x
Howard MR, Whitby D, Bahadur G, Suggett F, Boshoff C, et al.: Detection of human herpesvirus 8 DNA in semen from HIV-infected individuals but not healthy semen donors. AIDS 1997, 11: F15-19. 10.1097/00002030-199702000-00001
Kapranos N, Petrakou E, Anastasiadou C, Kotronias D: Detection of herpes simplex virus, cytomegalovirus, and Epstein-Barr virus in the semen of men attending an infertility clinic. Fertil Steril 2003,79(Suppl 3):1566-1570.
Kaspersen MD, Larsen PB, Kofod-Olsen E, Fedder J, Bonde J, et al.: Human herpesvirus-6A/B binds to spermatozoa acrosome and is the most prevalent herpesvirus in semen from sperm donors. PLoS One 2012, 7: e48810. 10.1371/journal.pone.0048810
Monini P, de Lellis L, Fabris M, Rigolin F, Cassai E: Kaposi’s sarcoma-associated herpesvirus DNA sequences in prostate tissue and human semen. N Engl J Med 1996, 334: 1168-1172. 10.1056/NEJM199605023341805
Lisco A, Munawwar A, Introini A, Vanpouille C, Saba E, et al.: Semen of HIV-1-infected individuals: local shedding of herpesviruses and reprogrammed cytokine network. J Infect Dis 2012, 205: 97-105. 10.1093/infdis/jir700
McGowan MP, Hayes K, Kovacs GT, Leydon JA: Prevalence of cytomegalovirus and herpes simplex virus in human semen. Int J Androl 1983, 6: 331-336. 10.1111/j.1365-2605.1983.tb00547.x
Michou V, Liarmakopoulou S, Thomas D, Tsimaratou K, Makarounis K, et al.: Herpes virus infected spermatozoa following density gradient centrifugation for IVF purposes. Andrologia 2012, 44: 174-180. 10.1111/j.1439-0272.2010.01121.x
Neofytou E, Sourvinos G, Asmarianaki M, Spandidos DA, Makrigiannakis A: Prevalence of human herpes virus types1–7in the semen of men attending an infertility clinic and correlation with semen parameters. Fertil Steril 2009, 91: 2487-2494. 10.1016/j.fertnstert.2008.03.074
Rinaldo CR Jr, Kingsley LA, Ho M, Armstrong JA, Zhou SY: Enhanced shedding of cytomegalovirus in semen of human immunodeficiency virus-seropositive homosexual men. J Clin Microbiol 1992, 30: 1148-1155.
Rintala MAM, Grénman SE, Pöllänen PP, Suominen JJO, Syrjänen SM: Detection of high-risk HPV DNA in semen and its association with the quality of the semen. Int J STD AIDS 2004, 15: 740-743. 10.1258/0956462042395122
Rohde V, Erles K, Sattler HP, Derouet H, Wullich B, et al.: Detection of adeno-associated virus in human semen: does viral infection play a role in the pathogenesis of male infertility? Fertil Steril 1999, 72: 814-816. 10.1016/S0015-0282(99)00363-5
Thomas R, Macsween KF, McAulay K, Clutterbuck D, Anderson R, et al.: Evidence of shared Epstein-Barr viral isolates between sexual partners, and low level EBV in genital secretions. J Med Virol 2006, 78: 1204-1209. 10.1002/jmv.20682
Wald A, Matson P, Ryncarz A, Corey L: Detection of herpes simplex virus DNA in semen of men with genital HSV-2 infection. Sex Transm Dis 1999, 26: 1-3. 10.1097/00007435-199901000-00001
Bantel-Schaal U, Neumann-Haefelin D, Schieferstein G: Cytomegalovirus is absent from semen of a population of men seeking fertility evaluation. J Infect Dis 1993, 168: 518-519. 10.1093/infdis/168.2.518
Bresson JL, Clavequin MC, Mazeron MC, Mengelle C, Scieux C, et al.: Risk of cytomegalovirus transmission by cryopreserved semen: a study of 635 semen samples from 231 donors. Hum Reprod 2003, 18: 1881-1886. 10.1093/humrep/deg362
Diafouka F, Foulongne V, Hauhouot-Attoungbre M-L, Monnet D, Segondy M: Cytomegalovirus DNA in semen of men seeking fertility evaluation in Abidjan, Côte d’Ivoire. Eur J Clin Microbiol Infect Dis 2007, 26: 295-296. 10.1007/s10096-007-0271-y
Eggert-Kruse W, Reuland M, Johannsen W, Strowitzki T, Schlehofer JR: Cytomegalovirus (CMV) infection–related to male and/or female infertility factors? Fertil Steril 2009, 91: 67-82. 10.1016/j.fertnstert.2007.11.014
Handsfield HH, Chandler SH, Caine VA, Meyers JD, Corey L, et al.: Cytomegalovirus infection in sex partners: evidence for sexual transmission. J Infect Dis 1985, 151: 344-348. 10.1093/infdis/151.2.344
Lang DJ, Kummer JF: Cytomegalovirus in semen: observations in selected populations. J Infect Dis 1975, 132: 472-473. 10.1093/infdis/132.4.472
Levy R, Najioullah F, Keppi B, Thouvenot D, Bosshard S, et al.: Detection of cytomegalovirus in semen from a population of men seeking infertility evaluation. Fertil Steril 1997, 68: 820-825. 10.1016/S0015-0282(97)00340-3
Mansat A, Mengelle C, Chalet M, Boumzebra A, Mieusset R, et al.: Cytomegalovirus detection in cryopreserved semen samples collected for therapeutic donor insemination. Hum Reprod 1997, 12: 1663-1666. 10.1093/humrep/12.8.1663
Naumenko VA, Tyulenev YA, Yakovenko SA, Kurilo LF, Shileyko LV, et al.: Detection of human cytomegalovirus in motile spermatozoa and spermatogenic cells in testis organotypic culture. Herpesviridae 2011, 2: 7. 10.1186/2042-4280-2-7
Shen CY, Chang SF, Yang SL, Wu CW, Yang YS, et al.: Cytomegalovirus is present in semen from a population of men seeking fertility evaluation. J Infect Dis 1994, 169: 222-223. 10.1093/infdis/169.1.222
Sherertz RJ, Peacock JE Jr, Sixbey JW, Folds JD, Bowdre JH, et al.: Nonurban male homosexuals: epidemiologic, immunologic and virologic characteristics. Am J Med Sci 1984, 288: 109-113. 10.1097/00000441-198410000-00003
Yang YS, Ho HN, Chen HF, Chen SU, Shen CY, et al.: Cytomegalovirus infection and viral shedding in the genital tract of infertile couples. J Med Virol 1995, 45: 179-182. 10.1002/jmv.1890450212
Looker KJ, Garnett GP: A systematic review of the epidemiology and interaction of herpes simplex virus types 1 and 2. Sex Transm Infect 2005, 81: 103-107. 10.1136/sti.2004.012039
Moore DE, Ashley RL, Zarutskie PW, Coombs RW, Soules MR, et al.: Transmission of genital herpes by donor insemination. JAMA 1989, 261: 3441-3443. 10.1001/jama.1989.03420230095034
Enright AM, Prober CG: Neonatal herpes infection: diagnosis, treatment and prevention. Semin Neonatol 2002, 7: 283-291.
Pallier C, Tebourbi L, Chopineau-Proust S, Schoevaert D, Nordmann P, et al.: Herpesvirus, cytomegalovirus, human sperm and assisted fertilization. Hum Reprod 2002, 17: 1281-1287. 10.1093/humrep/17.5.1281
DeTure FA, Drylie DM, Kaufman HE, Centifanto YN: Herpesvirus type 2: isolation from seminal vesicle and testes. Urology 1976, 7: 541-544. 10.1016/0090-4295(76)90204-1
Pagano JS: Is Epstein-Barr virus transmitted sexually? J Infect Dis 2007, 195: 469-470. 10.1086/510861
Meyohas MC, Marechal V, Desire N, Bouillie J, Frottier J, et al.: Study of mother-to-child Epstein-Barr virus transmission by means of nested PCRs. J Virol 1996, 70: 6816-6819.
Pellett PE, Spira TJ, Bagasra O, Boshoff C, Corey L, et al.: Multicenter comparison of PCR assays for detection of human herpesvirus 8 DNA in semen. J Clin Microbiol 1999, 37: 1298-1301.
Revello MG, Gerna G: Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev 2002, 15: 680-715. 10.1128/CMR.15.4.680-715.2002
Lang DJ, Kummer JF, Hartley DP: Cytomegalovirus in semen. Persistence and demonstration in extracellular fluids. N Engl J Med 1974, 291: 121-123. 10.1056/NEJM197407182910303
Monini P, Howard MR, Rimessi P, de Lellis L, Schulz TF, et al.: Human herpesvirus DNA in prostate and semen from HIV-negative individuals in Italy. AIDS 1997, 11: 1530-1532.
Frank TS, Himebaugh KS, Wilson MD: Granulomatous endometritis associated with histologically occult cytomegalovirus in a healthy patient. Am J Surg Pathol 1992, 16: 716-720. 10.1097/00000478-199207000-00010
Kowalik TF, Yurochko AD, Rinehart CA, Lee CY, Huang ES: Productive infection of human endometrial stromal cells by human cytomegalovirus. Virology 1994, 202: 247-257. 10.1006/viro.1994.1340
Griffiths PD, Baboonian C: A prospective study of primary cytomegalovirus infection during pregnancy: final report. Br J Obstet Gynaecol 1984, 91: 307-315. 10.1111/j.1471-0528.1984.tb05915.x
Fisher S, Genbacev O, Maidji E, Pereira L: Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: implications for transmission and pathogenesis. J Virol 2000, 74: 6808-6820. 10.1128/JVI.74.15.6808-6820.2000
Van den Veyver IB, Ni J, Bowles N, Carpenter RJ Jr, Weiner CP, et al.: Detection of intrauterine viral infection using the polymerase chain reaction. Mol Genet Metab 1998, 63: 85-95. 10.1006/mgme.1997.2651
Leong HN, Tuke PW, Tedder RS, Khanom AB, Eglin RP, et al.: The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. J Med Virol 2007, 79: 45-51. 10.1002/jmv.20760
Wyatt LS, Rodriguez WJ, Balachandran N, Frenkel N: Human herpesvirus 7: antigenic properties and prevalence in children and adults. J Virol 1991, 65: 6260-6265.
Caserta MT, Hall CB, Schnabel K, Lofthus G, McDermott MP: Human herpesvirus (HHV)-6 and HHV-7 infections in pregnant women. J Infect Dis 2007, 196: 1296-1303.
Chow SS, Craig ME, Jacques CF, Hall B, Catteau J, et al.: Correlates of placental infection with cytomegalovirus, parvovirus B19 or human herpes virus 7. J Med Virol 2006, 78: 747-756. 10.1002/jmv.20618
Hettmann A, Gerle B, Barcsay E, Csiszar C, Takacs M: Seroprevalence of HSV-2 in Hungary and comparison of the HSV-2 prevalence of pregnant and infertile women. Acta Microbiol Immunol Hung 2008, 55: 429-436. 10.1556/AMicr.55.2008.4.7
Baillargeon J, Piper J, Leach CT: Epidemiology of human herpesvirus 6 (HHV-6) infection in pregnant and nonpregnant women. J Clin Virol 2000, 16: 149-157. 10.1016/S1386-6532(99)00086-4
Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, et al.: Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 1992, 359: 76-79. 10.1038/359076a0
Steck T, Giess R, Suetterlin MW, Bolland M, Wiest S, et al.: Leukaemia inhibitory factor (LIF) gene mutations in women with unexplained infertility and recurrent failure of implantation after IVF and embryo transfer. Eur J Obstet Gynecol Reprod Biol 2004, 112: 69-73. 10.1016/S0301-2115(03)00315-4
Hu W, Feng Z, Teresky AK, Levine AJ: p53 regulates maternal reproduction through LIF. Nature 2007, 450: 721-724. 10.1038/nature05993
Trogstad LI, Eskild A, Bruu AL, Jeansson S, Jenum PA: Is preeclampsia an infectious disease? Acta Obstet Gynecol Scand 2001, 80: 1036-1038. 10.1034/j.1600-0412.2001.801112.x
Dejucq NJB: Viruses in the mammalian male genital tract and their effects on the reproductive system. Microbiol Mol Biol Rev 2001, 65: 208-231. 10.1128/MMBR.65.2.208-231.2001
The authors declare that they have no competing interests.
MDK surveyed literature and wrote the first draft of the article. PH organized the contents and submitted the article. Both authors read and approved the final manuscript.