Journal of Reproductive Immunology

55 (2002) 113–121
www.elsevier.com/locate/jreprimm

Viral infection of the trophoblast: time to take

a serious look at its role in abnormal
implantation and placentation?
Fabian Arechavaleta-Velasco, Hideki Koi,
Jerome F. Strauss III *, Samuel Parry
Center for Research on Reproduction and Women’s Health, Uni6ersity of Pennsyl6ania Medical Center,
1354 BRB II/III, 421 Curie Boule6ard, Philadelphia, PA 19104, USA
Received 4 June 2001; received in revised form 9 July 2001; accepted 10 July 2001

Abstract

Fragmentary evidence suggests that trophoblast viral infection may play a role in
placental dysfunction, leading to complications including spontaneous miscarriage,
preeclampsia, fetal growth restriction and preterm birth. Here, we review the mechanisms
underlying differentiation and gestational age-dependent infection of trophoblast cells and
the consequences of in vitro infection on trophoblast function. The relationship between
trophoblast infection by common viruses and pregnancy outcomes is also analyzed. We
conclude that there is sufficient evidence linking placental infection by common viruses,
including viruses thought to be non-pathogenic or to have low pathogenicity, to indicate
that this effect contributes to poor pregnancy outcome. © 2002 Elsevier Science Ireland
Ltd. All rights reserved.

Keywords: Trophoblast; Viral infection; Placental dysfunction

* Corresponding author. Tel.: + 1-215-898-0147; fax: + 1-215-573-5408.

E-mail address: jfs3@mail.med.upenn.edu (J.F. Strauss, III).

0165-0378/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 1 6 5 - 0 3 7 8 ( 0 1 ) 0 0 1 4 3 - 7
114 F. Arecha6aleta-Velasco et al. / Journal of Reproducti6e Immunology 55 (2002) 113–121

1. Introduction

Abnormal embryo implantation and placentation are thought to con-

tribute to pregnancy complications including spontaneous pregnancy loss,
preeclampsia, and intrauterine growth restriction. There has been consider-
able interest regarding the role of genetic and immunological factors in the
pathogenesis of abnormal nidation/placentation, but relatively little atten-
tion has been given to the impact of infection, particularly viral infection on
placentation. Although there has been some interest in the mechanisms of
vertical transmission of human immunodeficiency virus (HIV) in pregnancy,
investigation into the impact of placental infection by viruses that are well
known to cause pregnancy complications (e.g. cytomegalovirus; CMV) has
been limited. It is also unclear whether the potential for viral infection and
the attendant maternal immune response to viral infection may account for
the reported seasonal peaks of certain pregnancy complications. For exam-
ple, the incidence of viral infections such as parvovirus tend to vary with a
seasonal pattern, which could reflect the seasonality of preeclampsia (Wood-
worth et al., 1994; Rousham and Gracey, 1998; Wacker et al., 1998;
Cagnacci et al., 1999). Similarly, the increased incidence of preeclampsia in
primigravidas may reflect the innate immune response versus the acquired
immune response in multigravidas, but this has not engendered enthusiasm
among scholars in the field of reproductive medicine.
Despite the paucity of activity in this area, there is accumulating informa-
tion indicating that viral infection, including infection by viruses considered
to have little or no pathogenicity, can impair trophoblast function and
potentially contribute to pregnancy loss or to the presumed sequelae of
abnormal implantation (i.e. preeclampsia and intrauterine growth restric-
tion). The evidence for this notion, although fragmentary at this juncture,
includes: (1) in vitro studies demonstrating that trophoblast cells can be
infected by certain viruses; (2) in vitro experiments demonstrating that viral
infection can alter trophoblast gene expression, reduce trophoblast invasive
activity, and lead to apoptotic cell death; (3) reports that viral DNA can be
recovered from placental tissue from spontaneous miscarriages, pregnancies
complicated by preeclampsia, and amniotic fluid from pregnancies ending in
preterm birth; and (4) detection in maternal serum of IgM antibodies to
viruses in greater frequency in pregnancies complicated by preeclampsia and
preterm birth, suggesting pregnancy-associated infection.
Unfortunately, prospective studies of adequate statistical power exploring
any relationship between trophoblast viral infection and poor reproductive
outcome have yet to be conducted. This is not surprising given their
demanding nature requiring longitudinal monitoring from the earliest stages
of gestation in order to identify the time of infection, the kinetics of the
 F. Arecha6aleta-Velasco et al. / Journal of Reproducti6e Immunology 55 (2002) 113–121 115

maternal immune response, and the full spectrum of potential complications

ranging from early spontaneous pregnancy loss, inadequate placentation,
preterm birth or silent disease, and documentation of placental infection.
Here, we will briefly summarize the case for moving ahead and consider
some of the outstanding issues that need to be addressed regarding the
pathophysiology of virus–trophoblast interactions.

2. The susceptibility of extravillous trophoblast and villous cytotrophoblast

to viral infection: dependence on state of differentiation and gestational age

The study of trophoblast infection by viruses other than HIV has been
carried out with recombinant viral vectors used for gene transfer and, to a
limited extent, wild-type viruses (Norskov-Lauritsen et al., 1992; MacCal-
man et al., 1996; Hemmings et al., 1998; Parry et al., 1998). An advantage
of the use of recombinant viral vectors is that reporter genes like LacZ can
be introduced into the constructs, facilitating the identification of virus
uptake and viral gene expression. Human choriocarcinoma cells (BeWo and
JEG-3 cells lines which display properties of intermediate trophoblast),
extravillous trophoblast cells isolated from first trimester placentas, and
cytotrophoblasts isolated from term placentas, can be infected in vitro with
a variety of viruses including CMV, herpes simplex virus (HSV), adenovirus
and adeno-associated virus (AAV) (MacCalman et al., 1996; Parry et al.,
1998; Halwachs-Baumann et al., 1998; Fisher et al., 2000). However, as
trophoblasts differentiate in culture either spontaneously or under the
influence of 8-Br-cAMP, the ability of the cells to take up certain viruses
(adenovirus and HSV-1) is markedly reduced (MacCalman et al., 1996;
Parry et al., 1998). Thus, syncytiotrophoblast is relatively resistant to
infection by these viruses. Although the literature regarding trophoblast
infection by HIV contains some discrepant reports, it appears that chorio-
carcinoma cells as well as cytotrophoblast and intermediate trophoblast
cells in the first trimester can be infected by HIV, whereas term syncytiotro-
phoblast cannot (McGann et al., 1994; Mognetti et al., 2000; Sheikh et al.,
2000). Adeno-associated virus is an interesting exception to this pattern of
differentiation or gestational age-dependent susceptibility, and will be dis-
cussed later.
The susceptibility of trophoblast cells to viral infection, and the relative
resistance of differentiated trophoblast to infection by the viruses noted
above, is evidently determined by the expression pattern of receptors
mediating virus binding and entry. This has been best documented for
adenovirus where the knob domain of the viral fiber protein binds to the
coxsackievirus B and adenovirus receptor (CAR) (Bergelson et al., 1997).
116 F. Arecha6aleta-Velasco et al. / Journal of Reproducti6e Immunology 55 (2002) 113–121

Following binding to CAR, adenovirus is internalized by a process involv-

ing binding of the virus penton base to aVb3 or aVb5 integrins (Wickham
et al., 1993). CAR is expressed by choriocarcinoma cells and extravillous
trophoblast cells, but not by third trimester trophoblast cells and syncy-
tiotrophoblast (Koi et al., 2001). Preliminary studies indicate that the
susceptibility of trophoblast cells to infection by HSV is also determined by
the expression of its entry mediators (HveB and HveC) (Parry et al., 2000).
Adeno-associated virus is a small, single-stranded DNA parvovirus of the
dependovirus family, which causes a mild febrile disease in children, and it
is estimated that the prevalence of infection is quite high (40–80% of adults
are seropositive for AAV-2). There are six serotypes of the virus that infect
humans, the most prevalent being AAV-2. AAV integrates into the human
genome at chromosome 19q3.4–19ter. Indeed, AAV-2 DNA has been
found to be integrated into JEG-3, JAR, and BeWo choriocarcinoma cell
line DNA (Dutheil et al., 1997). As a dependovirus, AAV requires a helper
virus to replicate in cells that it infects. Helper viruses as well as stress can
reactivate integrated virus (Erles et al., 1999; Schlehofer and Dupressoir,
2000).
AAV can infect choriocarcinoma cells and extravillous trophoblast as
well as third trimester syncytiotrophoblast (Parry et al., 1998). In contrast
to adenovirus and HSV, pharmacologically induced differentiation of tro-
phoblast cells with 8-Br-cAMP rapidly (within minutes to hours) augments
AAV infection. The mechanism underlying this response has not been
established, but 8-Br-cAMP might influence the number of AAV binding
sites on the cell surface or the efficiency of virus entry. Although there are
contradictory reports, it appears that the primary receptor mediating AAV
binding to cells is the heparan sulfate proteoglycan (Summerford and
Samulski, 1998; Qiu et al., 2000); the aVb5 integrin and the fibroblast
growth factor receptor-1 are proposed to mediate virus entry (Summerford
et al., 1999; Qing et al., 1999; Qiu and Brown, 1999; Baranowski et al.,
2001).

3. Impact of viral infection on trophoblast function

There have been relatively few studies on the functional significance of

trophoblast viral infection. Several potentially important sequelae have been
described. Infection of first trimester trophoblast cells with HSV-1 and
CMV has been found to diminish cell surface HLA-G expression (Schust et
al., 1996; Jun et al., 2000). Although the consequence of this alteration in
gene expression is not known, it could alter the susceptibility of trophoblast
cells to the maternal immune surveillance system, ultimately engendering an
 F. Arecha6aleta-Velasco et al. / Journal of Reproducti6e Immunology 55 (2002) 113–121 117

immune response that could delete these cells. CMV infection has also been
shown to reduce the invasive activity of extravillous trophoblast cells in an
in vitro model of Matrigel penetration (Fisher et al., 2000). Infection of
extravillous trophoblast cells with adenovirus was shown to significantly
increase the apoptotic death of the cells, especially when the trophoblasts
were cocultured in the presence of decidual lymphocytes to simulate the
maternal immune response to viral infection (Koi et al., 2001). AAV-2
infection interferes with the in vitro development of mouse embryos,
causing arrest at the two-cell stage (Botquin et al., 1994), and in vivo
infection of pregnant mice with AAV-2 causes fetal demise. HIV infection
may also induce transcription that affects trophoblast endocrine function
(Huang and Miller, 2000).
Collectively, these findings suggest that early embryonic and trophoblas-
tic viral infection impairs implantation or placentation, possibly by eliciting
an anti-trophoblast cellular immune response resulting in apoptosis, re-
duced trophoblast invasion and remodeling of the decidua and uterine
arterial vessels, and arrest of early embryonic development. These observa-
tions are noteworthy given the fact that placental bed biopsies obtained
from pregnancies complicated by preeclampsia show reduced trophoblast
invasion and spiral artery remodeling as well as increased trophoblast
apoptosis (Zhou et al., 1993, 1997; DiFederico et al., 1999; Allaire et al.,
2000; Leung et al., 2001).
The exact mechanism by which viral infection alters trophoblast gene
expression or increases apoptosis in the face of maternal immune cells have
not been elucidated. Moreover, the role of viral infection on trophoblast
cytokine production remains to be explored. It is also not known whether
this is a generalized response to viral infection or whether there are
virus-specific trophoblast responses.

4. Do common viruses infect the placenta and cause pregnancy

complications?

A number of observational studies link placental and fetal viral infection

by supposedly non-or low pathogenic viruses with adverse pregnancy
outcomes. Adenovirus DNA has been detected in fetal specimens and
amniotic fluid from abnormal pregnancies, including fetal hydrops, fetal
growth restriction and oligohydramnios, but only rarely in normal control
pregnancies (Van den Veyver et al., 1998). AAV-2 DNA and protein are
more frequently detected in placental tissue derived from first trimester
spontaneous miscarriages than from first trimester pregnancy terminations
(Tobiasch et al., 1994). AAV DNA and protein were localized in the
118 F. Arecha6aleta-Velasco et al. / Journal of Reproducti6e Immunology 55 (2002) 113–121

syncytiotrophoblast of spontaneous pregnancy loss specimens. Moreover,

reproductive tissues of the former are more likely to be infected with human
papillomavirus (HPV), an AAV helper virus (Malhomme et al., 1997). In
our laboratory, maternal serum antibodies against AAV-2 and viral DNA
in placental samples were associated with spontaneous miscarriage and
preeclampsia, respectively (unpublished data). However, other authors
failed to detect AAV-2 DNA in placental and fetal tissues from sponta-
neous miscarriages or first trimester induced abortions (Friedman-Einat et
al., 1997). AAV-2 infection has also been associated with premature rupture
of membranes and preterm labor (Burguete et al., 1999).
Infection of extravillous trophoblast cells with pathogenic viruses (HSV-1,
HSV-2 and CMV) is also associated with spontaneous pregnancy loss
(Griffiths and Babbonian, 1984; Robb et al., 1986; Bujko et al., 1988). CMV
and HSV-2 were detected in more than half of placental tissue specimens
from growth restricted pregnancies in which pathological changes, including
villitis and retarded villous maturation, were noted. These viral pathogens
were detected in less than 10% of placentas showing no pathology (Griffiths
and Babbonian, 1984; Brown et al., 1987).
Although collectively these findings suggest that placental viral infection
can impair trophoblast function and result in an unfavorable pregnancy
outcome, these studies do not establish that the poor outcomes result from
infection acquired during pregnancy. In the case of AAV, latent virus may
have been activated resulting in placental infection. In addition, the impact
of infection of the embryo/fetus itself as opposed to trophoblast/placental
infection cannot be ascertained from the existing literature.

5. Expression of integrated viral genes and placental function

Viral infection resulting in integration of viral DNA sequence into the

human genome and subsequent trophoblast expression of virus-encoded
genes may have an important influence on trophoblast function. Anyone
who has randomly sequenced cDNAs from human placental cDNA li-
braries frequently encounter expressed retroviral transcripts. Originally
thought to be archeological relics, these transcripts may reflect a suite of
genes that have been co-opted by trophoblast to perform specific functions.
One prominent example is syncytin, a captive retroviral envelope protein
implicated in the process of syncytiotrophoblast formation (Mi et al., 2000).
The transcription of these integrated viral genes in the placenta may be an
important driving force with respect to diversity in placental structure and
function. Whether integrated AAV DNA sequences or re-activated virus
have an impact on placental function remains to be determined.
 F. Arecha6aleta-Velasco et al. / Journal of Reproducti6e Immunology 55 (2002) 113–121 119

6. Conclusions

Increasing amounts of evidence indicate that cytotrophoblast and ex-

travillous trophoblast are susceptible to infection by common viruses,
including those thought to have no or low pathogenicity, and that viral
infection early in pregnancy can impair critical trophoblast functions. These
findings provide a solid scientific basis for continued critical investigation of
the role of common viral infection in early pregnancy loss and pregnancy
complications related to placental dysfunction.

Acknowledgements

Research in the author’s laboratory was supported by N.I.H. grants K12

HD01265, D43 TW01272 and a grant from the Bill and Melinda Gates
Foundation.

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