Table 2.

Studies on AAV infection and reproductive system disorders in humans

References	Year	Country	Study population	Samples	Results	Conclusions
[46]	1994	France	108 sera (24 women presenting with early miscarriage; 23 women with lesions of the cervix uteri; 61 controls). 30 biopsies of the cervix uteri (10 normal tissue; 5 lesions of the endometrium; 15 cervical cancer). 30 curettage material of spontaneous abortion.	Serum; biopsy of uterus; tissue material from spontaneous abortion	AAV type 2 DNA was amplified in histological sections of 19 of 30 biopsies of the uterine mucosa. AAV DNA was detected in abortion material during the first trimester of pregnancy (12/30 cases were positive) but not in material of abortion from the second or third trimester (9 cases). The prevalence of IgM antibodies to AAV type 2 was elevated in cases of spontaneous abortion (first trimester, 29.1%), and in women with cervical cancer (30.4%) compared to the control group (9.9%).	In view of the presence of AAV DNA and proteins in placenta tissue, serological tests might be useful to assess further the hypothesis of a possible role of AAV infection in spontaneous abortion.
[75]	1997	France	13 histological sections of the cervix uteri; 9 endometrium biopsies; 26 samples of abortion material; 2 samples of curettage material of extrauterine gravidity; 1 sample of socially indicated abortion.	Cervical tissue; abortion material	HPV DNA was detected in approximately 60% of paraffin sections from uterus biopsies and cervical lesions containing AAV type 2 DNA and in approximately 70% of material from early miscarriage.	HPV may be a helper virus for AAV.
[77]	1997	Israel	15 nasopharyngeal aspirates from symptomatic patients; 7 swab or fluid specimens from vesicles of patients suspected of having varicella-zoster virus infections; 21 human papilloma virus-positive genital biopsy specimens; 61 genital swab specimens from women suspected of having herpes simplex virus; 62 samples of first trimester aborted material (38 spontaneous and 24 induced abortions); 11 samples of chorionic villi; 3 lots of cultured human embryonic cells.	Different clinical samples.	AAV type 2 sequences were detected only in samples (n = 11) taken from the genital tracts of women suspected of having herpes infection and not in any of the other types of samples.	Our study demonstrates the presence of AAV in the female genital tract. However, in contrast to a previous report, we did not find solid evidence of its replication in maternal or embryonal tissues from the first trimester of pregnancy. The questions of a potential pathogenic etiology of AAV and the interaction with HSV remain open.
[79]	1999	Germany	Men with diagnosed infertility = 30 Control = 8	Semen	AAV DNA was detected in 30% (9/30) of the ejaculates from the infertile men. No AAV DNA was found in the ejaculates from the 8 control subjects. In 8 of 9 samples, AAV DNA could be found only in the spermatozoal fraction of the specimen. Seven of 9 semen specimens that contained viral DNA also demonstrated oligoasthenozoospermia. Both AAV and HPV DNA was found in the spermatozoal fraction of 3 of 30 specimens.	The data demonstrate for the first time the occurrence of AAV infection in human semen. Sperm motility seems to be affected by the presence of AAV.
[80]	2001	Germany	95 men (with history of infertility = 73; without history of infertility = 22) 17 men (with malignant melanoma = 3; benign tumor = 5; stone = 1; adenoma of the prostate = 1; no diagnosis = 7). 38 azoospermic men. 57 female partners.	Semen; cervical smear; urethral smear; testicular biopsy	AAV DNA was detected in 38% (28/73) of ejaculates from men with abnormal semen analyses and in 4.6% of normal semen samples (1/22, P > 0.003). In testes, AAV DNA was detected in 10 out of 38 biopsies from infertile men (26%), and in 2 out of 8 orchidectomy samples.	The data show an increased incidence of AAV infection with abnormal semen analysis. Detection of AAV DNA in the testes might point to a role for AAV infection in male infertility, possibly by interfering with spermatozoa development.
[71]	2002	Brazil	78 paraffin-embedded tissue samples, including histologically confirmed hydatiform moles (42 complete, 4 partial, 3 invasive, 14 choriocarcinomas, and 15 materials from spontaneous abortion.	Tissue of hydatiform moles, choriocarcinomas, and spontaneous abortion.	AAV DNA was found in 43 samples (28/49 hydatiform moles, 4/14 choriocarcinomas, 11/15 miscarriage material).	These findings confirm AAV infection of embryo-derived tissue in humans and further suggest a role of AAV in miscarriage and trophoblastic disease.
[78]	2004	Croatia	108 women admitted to the hospital for threatened miscarriage.	Placental tissue	No detection of AAV DNA.	No influence of AAV infection in miscarriages during the first trimester of pregnancy.
[81]	2004	Germany	2 patients with prostate cancer.	Testis tissue	AAV DNA is present in an integrated form in testis tissue. A detailed analysis revealed integration within sequences of the so-called AAVS1 region on chromosome 19.	AAV DNA can integrate also after natural infection, and that integration occurs within the AAVS1 region, at least in some cases.
[70]	2006	USA	Cases of preeclampsia = 40 Control = 27	Histological sections from the basal plate region of placentas, and trophoblast cells.	AAV type 2 DNA was found more frequently in trophoblast cells from cases of severe preeclampsia (22/40) than from normal term deliveries (5/27, P = 0.002).	AAV infection is a previously unidentified cause of placental dysfunction.
[69]	2008	USA	Cases = 78 (34 spontaneous abortions; 24 spontaneous preterm deliveries; 20 women with at least one outcome usually attributed to placental dysfunction) Control = 106	Serum	First trimester maternal IgM seropositivity to AAV type 2 was 5.6 times more prevalent among pre-eclampsia/IUGR/stillbirth cases (P = 0.0004) and 7.6 times more prevalent among preterm deliveries (P < 0.0001) than among controls. AAV infection (IgG seropositivity) was not associated with adverse pregnancy outcomes.	Primary or reactivated AAV infection (maternal IgM seropositivity) early in pregnancy was associated with adverse reproductive outcomes associated with placental dysfunction, including pre-eclampsia, stillbirth, and spontaneous preterm delivery.
[72]	2010	Brazil	Spontaneous abortion group = 68 Intentional abortion group = 13	Decidual and chorionic tissues.	AAV type 2 was detected in 28.4% (23/81) of the abortion cases for at least one of the decidual or ovular fragments, 32.3% (22/68) of the spontaneous and 7.7% (1/13) of intentional abortions.	The presence of AAV in decidual or trophoblastic cells in cases of abortion, as observed by in situ hybridization, implies that the virus could jeopardize the pregnancy. The significant predominance in spontaneous cases suggests possibly a causal association between AAV and abortion.
[82]	2012	Germany	146 male and 134 female partners of asymptomatic subfertile couples.	Semen samples and endocervical material	AAV DNA was detected in 20 out of 134 (14.9%) cervical swabs and in 29 out of 146 (19.9%) semen samples. 3.8% (5/133) couples were AAV DNA positive in both semen and endocervical materials. The presence of AAV DNA in semen was not significantly related to semen quality, nor was it coupled to the presence of AAV in the endocervical material of female partners. AAV DNA in endocervical material was not related to a reduced quality of cervical mucus or to other female infertility factors.	The presence of AAV DNA in semen samples or endocervical swabs showed no significant association with clinically relevant infertility factors.
[45]	2019	Iran	Therapeutic abortions = 81 Spontaneous abortions = 83	Placental tissues	62 (38.2%) of 164 abortions were AAV positive, including 35 (21.6%) spontaneous abortions and 27 (16.6%) therapeutic abortions.	There was no statistically significant difference between the presence of the AAV genome in spontaneous and therapeutic abortions.

IUGR, intrauterine growth restriction