Elsevier

Placenta

Volume 25, Supplement, April 2004, Pages S16-S25
Placenta

Expression and Functions of Human Endogenous Retroviruses in the Placenta: An Update

https://doi.org/10.1016/j.placenta.2004.01.012Get rights and content

Abstract

The placenta is unique amongst normal tissues in transcribing many different human endogenous retrovirus (HERV) families at high levels and this has led to the suggestion that HERVs may fulfil important functions in reproduction. This review discusses our current knowledge of the placental expression of HERVs, in particular the envelope proteins of ERV3 and HERV-W which may have critical roles in placental function.

Introduction

Endogenous retroviruses (ERVs) are complete or degenerate retroviral sequences which are normal components of the DNA of all cells. ERVs have been described in all vertebrates studied, and in humans, comprise about 5 per cent of the genome [1]. They are thought to be the remnants of ancient germ cell infections by now-extinct exogenous retroviruses. Phylogenetic analyses indicate that the integrations occurred early in primate evolution, with the various human endogenous retrovirus (HERV) families appearing at different times ranging from less than ten to 60 million years ago. The largest wave of insertions occurred approximately 30 million years ago, after the separation of the Old and New World monkeys [2].

HERVs are simple retroviruses consisting of gag, pol and env genes which code for the capsid components (nucleocapsid, capsid and matrix proteins), enzymes (reverse transcriptase (RT), ribonuclease H (RNaseH), integrase andprotease), and envelope protein respectively. These are flanked by regulatory regions known as long terminal repeats (LTRs) which contain a tRNA primer binding site (for priming reverse transcription), promoter and enhancer sequences, and RNA processing signals (Figure 1). HERV families are most commonly defined by the tRNA complementary to their putative primer binding site, using the one letter code for the tRNA's corresponding amino acid. So for example, the HERV-W family would be primed by tryptophan tRNA. Most HERV envelope proteins have a similar structure with surface and transmembrane portions. The transmembrane domain contains regions with potential fusogenic and immunosuppressive properties (Figure 2). The latter region is conserved amongst retroviruses and a corresponding synthetic peptide, CKS-17, has numerous immunomodulatory effects in vitro (Figure 3) [3], [4]. However, the ancient origin of HERVs has allowed the gradual accumulation of mutations which have abrogated the protein coding potential of many and, to date, there is scant evidence for the existence of infectious forms [5], [6]. Thousands of solitary LTRs are also found. These have resulted from homologous recombination between two proviral LTRs with deletion of the intervening viral genes.

The significance and consequences of the presence of HERVs in our genome have been the subject of extensive speculation and investigation. HERVs have been implicated in a wide variety of processes, both pathological, for example autoimmune disease and neoplasia, and physiological, including placental function and protection from exogenous retroviral infection [7], [8], [9], [10], [11], [12], [13]. One possible effect is mutagenesis at the insertion site and subsequent genomic instability since the latter is associated with repetitive sequences such as HERVs. HERV LTRs may affect the transcriptional regulation of neighbouring cellular genes and there is also growing evidence for the expression of retroviral proteins although their functions are incompletely understood.

The RNA expression of various HERV families has now been studied in an extensive range of cell types, tissues and diseases. From these investigations it has become apparent that the placenta is unique amongst normal tissues in both the diverse range of HERV transcripts and their high level of expression. This review will discuss the evidence for the placental expression of HERVs with particular emphasis on the envelope proteins of HERV-W and ERV3 for which interesting functional roles are emerging.

Section snippets

Placental retrovirus-like particles

One of the first hints that the placenta might be a site of HERV expression was the detection of retrovirus-like particles (RVLPs) in the villi of term placenta by electron microscopy [14]. This was corroborated by a number of further studies [15]. The percentage of placentae in which particles were detected varied quite considerably between reports, but all were consistent in their descriptions of the particle morphology, and location at the basal border of the syncytiotrophoblast where they

Cross-reactivity of trophoblast with animal retroviral antigens

Other early studies focussed on the apparent cross-reactivity between placental antigens and animal retroviruses. For example, five of six pregnant women showed cell-mediated immune reactivity to baboon endogenous virus (BaEV)-infected human fibroblasts [20]. Furthermore, an antiserum against syncytiotrophoblast plasma membrane reacted with cell lines producing BaEV and Mason–Pfizer monkey virus (M-PMV) [21]. Conversely, antibodies to BaEV and M-PMV displayed complement-dependent cytotoxicity

ERV3

ERV3 is a single copy HERV found on chromosome seven [27]. The primer binding site is most complementary to mouse arginine tRNA therefore it is alternatively known as HERV-R [28]. Its gag and pol genes have in-frame stop codons. Although env has a long ORF this is prematurely terminated in the transmembrane region, truncating the hydrophobic domain which anchors the protein in the cell membrane. Therefore, ERV3 Env may exist as a soluble molecule [29].

The transcription of ERV3 was examined in

HERV-W

Several studies have now provided evidence that HERV-W env is expressed almost exclusively in the placenta. Northern analysis of 23 normal tissues detected 8 kb and 4 kb transcripts in term placenta with much lower levels in the testis and no evidence for expression in any other tissue [38]. The more sensitive technique of quantitative PCR revealed HERV-W env mRNA in several normal tissues but confirmed restriction of high level transcription to the placenta [39]. In situ hybridization

HERV-FRD

Two recent publications have provided exciting evidence for a further placental envelope protein with possible functional importance. HERV-FRD family members were first identified in RVLPs produced by the breast carcinoma cell line T47-D by RT–PCR with degenerate pol primers and were named according to the first three amino acids of the deduced protein coding sequence [54]. A HERV-FRD env gene was subsequently identified during screening of the genome for potential complete coding Env proteins

Possible roles of HERVs in reproduction

To summarize, in addition to the abundance of HERV transcripts there is growing evidence for the expression of certain HERV proteins in the placenta. These products may have a variety of physiological roles: the envelope of HERV-W seems to be involved in cell fusion to form the syncytium and ERV3 Env is associated with cytotrophoblast differentiation.

In the Metavirus hypothesis, Villareal proposed that all mammals must express ERVs in extra-embryonic tissues to suppress local immune recognition

References (113)

  • X. Lee et al.

    Downregulation of placental syncytin expression and abnormal protein localization in pre-eclampsia

    Placenta

    (2001)
  • Y. Kudo et al.

    Characterization of amino acid transport systems in human placental basal membrane vesicles

    Biochim Biophys Acta

    (1990)
  • R. Kekuda et al.

    Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter B0from a human placental choriocarcinoma cell line

    J Biol Chem

    (1996)
  • Y. Kudo et al.

    Changes in expression and function of syncytin and its receptor, amino acid transport system B0(ASCT2), in human placental choriocarcinoma BeWo cells during syncytialisation

    Placenta

    (2002)
  • I. Knerr et al.

    Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome

    Am J Obstet Gynecol

    (2002)
  • Y. Kudo et al.

    Hypoxia alters expression and function of syncytin and its receptor during trophoblast fusion of human placental BeWo cells: implications for impaired trophoblast syncytialisation in pre-eclampsia

    Biochim Biophys Acta

    (2003)
  • S. Akira et al.

    Recognition of pathogen-associated molecular patterns by TLR family

    Immunol Lett

    (2003)
  • C. Kjellman et al.

    HERV-F (XA34) is a full-length human endogenous retrovirus expressed in placental and fetal tissues

    Gene

    (1999)
  • T. Johansen et al.

    Members of the RTVL-H family of endogenous retrovirus-like elements are expressed in placenta

    Gene

    (1989)
  • Y. Hirose et al.

    Presence of env genes in members of the RTVL-H family of human endogenous retrovirus-like elements

    Virology

    (1993)
  • A.C. Andersson et al.

    Elevated levels of the endogenous retrovirus ERV3 in human sebaceous glands

    J Invest Dermatol

    (1996)
  • A.C. Andersson et al.

    Developmental expression of HERV-R (ERV3) and HERV-K in human tissue

    Virology

    (2002)
  • Initial sequencing and analysis of the human genome

    Nature

    (2001)
  • E.D. Sverdlov

    Retroviruses and primate evolution

    Bioessays

    (2000)
  • G. Cianciolo et al.

    Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins

    Science

    (1985)
  • K. Nakagawa et al.

    The potential roles of endogenous retroviruses in autoimmunity

    Immunol Rev

    (1996)
  • T. Christensen et al.

    A transmissable human endogenous retrovirus

    AIDS Res Hum Retroviruses

    (2002)
  • P.M. Johnson et al.

    Endogenous retroviral expression in human placenta

    Am J Reprod Immunol

    (1990)
  • H. Herbst et al.

    Expression of human endogenous retrovirus K elements in germ cell and trophoblastic tumours

    Am J Pathol

    (1996)
  • D. Fox

    Why we don't lay eggs

    New Scientist

    (1999)
  • P.M. Schneider et al.

    The endogenous retroviral insertion in the human complement C4 gene modulates the expression of homologous genes by antisense inhibition

    Immunogenetics

    (2001)
  • F.W. Wang-Johannig et al.

    Expression of human endogenous retrovirus K envelope transcripts in human breast cancer

    Clin Cancer Res

    (2001)
  • V.G. Ponferrada et al.

    The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus

    Arch Virol

    (2003)
  • S.S. Kalter et al.

    C-type particles in normal human placentas

    J Natl Cancer Inst

    (1973)
  • S. Panem

    C-type virus expression in the placenta

    Curr Top Pathol

    (1979)
  • T.W. Lyden et al.

    Ultrastructural characterization of endogenous retrovirus particles isolated from normal human placentas

    Biol Reprod

    (1994)
  • R. Löwer et al.

    Identification of human endogenous retroviruses with complex mRNA expression and particle formation

    Proc Natl Acad Sci U S A

    (1993)
  • M.S. Hirsch et al.

    Immunity to antigens associated with primate C-type oncoviruses in pregnant women

    Science

    (1978)
  • L. Thiry et al.

    Heterologous antiserum to human syncytiotrophoblast membrane is cytotoxic to retrovirus-producing cells and to some cancer cell lines

    Am J Reprod Immunol

    (1981)
  • J. Suni et al.

    Retrovirus p30-related antigen in human syncytiotrophoblasts and IgG antibodies in cord-blood sera

    Int J Cancer

    (1981)
  • S. Maeda et al.

    Immunohistologic detection of antigen related to primate type C retrovirus p30 in normal human placentas

    Am J Pathol

    (1983)
  • L.B. Jerabek et al.

    Detection and immunochemical characterization of a primate type C retrovirus-related p30 protein in normal human placentas

    Proc Natl Acad Sci U S A

    (1984)
  • T. Wahlström et al.

    Monoclonal antibody defining a human syncytiotrophoblastic polypeptide immunologically related to mammalian retrovirus structural protein p30

    Placenta

    (1984)
  • C.D. O'Connell et al.

    The LTR sequences of a novel human endogenous retrovirus

    Science

    (1984)
  • N. Kato et al.

    Absence of expression of a human endogenous retrovirus is correlated with choriocarcinoma

    Int J Cancer

    (1988)
  • M.T. Boyd et al.

    The human endogenous retrovirus ERV-3 is upregulated in differentiating placental trophoblast cells

    Virology

    (1993)
  • M. Shibata

    Study on the specificity of a monoclonal antibody against recombinant envelope proteins of a human endogenous retrovirus, ERV3

    Hokkaido Igaku Zasshi

    (1996)
  • J.-M. Li et al.

    The expression of human endogenous retrovirus-3 in fetal cardiac tissue and antibodies in congenital heart block

    Clin Exp Immunol

    (1996)
  • N. de Parseval et al.

    Physiological knock out of the envelope gene of the single-copy ERV-3 human endogenous retrovirus in a fraction of the caucasian population

    J Virol

    (1998)
  • S. Mi et al.

    Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis

    Nature

    (2000)
  • Cited by (0)

    View full text