1 Department of Medical Microbiology and Parasitology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA
2 Center for Animal Biotechnology and Genomics, and Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
Correspondence
Massimo Palmarini
mpalmari{at}vet.uga.edu
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ABSTRACT |
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Introduction |
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ERVhost interactions
Eukaryotic transposons can spread rapidly in sexual species in the absence of positive selection at the cellular or organism level (Hickey, 1982). Thus, ERVs could have survived in the genome of eukaryotes without furnishing any obvious beneficial effect. However, some positive (and more rarely negative) roles for ERVs have been described and many more hypothesized. In general, ERVs are proposed to contribute in shaping the genome of the host and influencing gene expression by leading chromosomal rearrangements through homologous recombination between distant loci (Hughes & Coffin, 2001
) and by directly influencing gene expression (Ting et al., 1992
).
Interesting scenarios are envisaged for two human ERVs, ERV-3 and HERV-W (Human endogenous retrovirus W). ERV-3 (Venables et al., 1995) is conserved throughout primate evolution and is highly expressed in the trophoblast of the placenta (Boyd et al., 1993
). The similarity between a portion of the transmembrane (TM) glycoprotein of ERV-3 and a putative immunosuppressive region (termed p15E) (Haraguchi et al., 1995
) of gammaretroviruses led to the speculation that ERV-3 may protect the foetus from immune attack by the mother (Venables et al., 1995
). An even more intriguing example on how an ERV could be beneficial to its host is represented by HERV-W. HERV-W is specifically expressed in the syncytiotrophoblast of the human placenta. The HERV-W envelope protein, like many retroviral envelope proteins, induces formation of syncytia when expressed in vitro, thereby favouring the hypothesis that HERV-W is involved in human placental morphogenesis (Blond et al., 2000
; Mi et al., 2000
; Frendo et al., 2003
).
ERVs may also protect the host against infection by related exogenous retroviruses. For example, ERV (ev) loci of chickens (subgroup E) express envelope proteins that confer resistance to Rous sarcoma virus subgroup E infection, presumably by receptor interference (Payne & Pani, 1971). A similar situation has been observed in some feral mice, wherein the fv-4r locus blocks ecotropic receptors for Murine leukaemia virus (MLV) through an endogenous ecotropic gp70 synthesis (Kozak et al., 1984
).
An interference mechanism at the levels of post-entry and pre-integration is present in some strains of mice possessing the MLV-resistant locus fv-1 (Lilly, 1970). This locus was cloned, sequenced, and found to be related to HERV-L gag, an ERV only weakly related to MLV (Best et al., 1996
; Stoye, 1998
; Towers et al., 2000
). The precise mechanism of action of Fv-1 remains to be elucidated.
Endogenous interference through the immune system is well established in the Mouse mammary tumour virus model (MMTV) through the expression of a superantigen (Golovkina et al., 1992; Held et al., 1993
).
ERVs can also have detrimental effects and have been associated with some human diseases but for space limitations this topic will not be covered here.
The exogenous and pathogenic Jaagsiekte sheep retrovirus
Jaagsiekte sheep retrovirus (JSRV) is an exogenous and pathogenic retrovirus (Palmarini & Fan, 2001). JSRV is the cause of ovine pulmonary adenocarcinoma (OPA), a major infectious disease of sheep (Sharp, 1987
; Sharp & Angus, 1990
; DeMartini & York, 1997
; Palmarini et al., 1997
).
The JSRV genome has a simple genetic organization, characteristic of the replication-competent betaretroviruses (Hunter et al., 2000), containing the canonical structural retroviral genes gag, pro, pol and env (York et al., 1991
, 1992
; Palmarini et al., 1999a
) (Fig. 1
). The gag gene encodes the structural proteins of the viral core; pro and pol encode virion-bound enzymes (PR, RT and IN); and the env gene encodes the proteins in the envelope (surface and transmembrane).
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Another exogenous betaretrovirus related to JSRV and enJSRVs is ENTV (Enzootic nasal tumour virus) (Cousens et al., 1996, 1999
). The biology of ENTV is very similar to the highly related JSRV, including the capacity of ENTV Env to transform rodent fibroblasts in vitro (Alberti et al., 2002
; Dirks et al., 2002
).
Endogenous betaretroviruses of sheep related to JSRV
Sheep harbour in their genome about 20 copies of endogenous betaretroviruses (York et al., 1992; Hecht et al., 1994
, 1996
; DeMartini et al., 2003
) highly related to the exogenous and pathogenic JSRV (hence the name enJSRVs) (York et al., 1992
; De las Heras et al., 1993
; DeMartini & York, 1997
; Palmarini et al., 1997
, 1999a
). The genome of the enJSRVs loci is highly related to JSRV with 9098 % identity at the amino acid level in most parts of the genome (Bai et al., 1996
, 1999
; Palmarini et al., 1996a
, 2000b
; Rosati et al., 2000
).
We isolated, sequenced and functionally characterized three complete enJSRV proviruses (enJS56A1, enJS5F16 and enJS59A1) (Palmarini et al., 2000b) derived from a sheep genomic DNA
phage library. All three proviruses contained open reading frames encoding at least one or more structural genes. enJS56A1 is a virtually full-length provirus with open reading frames for gag, as well as most of pol and env (Fig. 1
). In transiently transfected cells, enJS56A1 is unable to release viral particles, even when expressed under control of the CMV immediate early promoter (pCMV2enJS56A1) (Palmarini et al., 2000b
). The use of JSRV/enJS56A1 chimeras determined that the main defect for particle formation resided in the first two-thirds of gag. Two short regions (VR1 and VR2) were identified in the enJS56A1 gag that contained major differences between ovine endogenous and exogenous betaretroviruses. In particular, VR1 contains a proline-rich region with SH2 and SH3 domains that are present in both JSRV and ENTV, but are absent in the homologous regions of the enJSRV proviruses. VR1 and VR2 belong to JSRV p23 (M. Mura & M. Palmarini, unpublished), a previously identified virion protein (Palmarini et al., 1999b
). A chimeric exogenous JSRV construct, wherein a region including the VR1 (Gag amino acid residues 89142) was replaced with the homologous region from the endogenous enJS56A1, is unable to produce viral particles in the supernatant (M. Mura & M. Palmarini, unpublished results). Thus, the VR1 region (or amino acid residues immediately adjacent the VR1) is a determinant for the release of JSRV viral particles. Understanding the nature of this defect is particularly important, as enJS56A1 also blocks the release of viral particles from the exogenous JSRV, underlining a novel mechanisms of retroviral interference acting late in the replication cycle (see below).
Besides VR1 and VR2, a third region (VR3) located in the carboxy-terminal portion of the transmembrane (TM) protein of the viral envelope, is divergent between the exogenous JSRV and enJSRV sequences (Palmarini et al., 2000b). Our studies indicate that this region is a main determinant of JSRV oncogenesis (see below) (Palmarini et al., 2001b
; Alberti et al., 2002
; Chow et al., 2003
; Zavala et al., 2003
).
enJSRVs interfere with exogenous JSRV entry by receptor interference
One of the possible reasons explaining the widespread fixation of ERVs in the mammalian germline is to protect the host from infection by related exogenous and pathogenic retroviruses. We hypothesized that enJSRVs interfered with the exogenous JSRV by receptor competition. The cellular receptor for JSRV was recently identified as the product of the hyaluronidase-2 (hyal-2) gene (Rai et al., 2000, 2001
). enJSRVs can also utilize Hyal-2 as a cellular receptor, based on assays using retroviral vectors pseudotyped by the enJS5F16 envelope (Spencer et al., 2003
). To assess whether enJSRVs could interfere with JSRV at entry, the enJS5F16 Env was stably expressed in an ovine endometrial stromal cell line (oST-enEnv). The oST cell line was established from sheep uterine endometrial stroma cells that do not express enJSRVs. The oST-enEnv cell line was approximately 300-fold less infectable than the parental oST cell line by exogenous JSRV Env pseudotyped retroviral vectors. Collectively, these results support the hypothesis that enJSRVs can interfere with the exogenous and pathogenic JSRV at the level of virus entry (Spencer et al., 2003
).
enJSRVs interfere with JSRV late in the replication cycle: a novel mechanism of retroviral interference
As explained previously, ERVs have been found to interfere with their exogenous counterpart at the entry (e.g. the fv-4 locus) (Kozak et al., 1984) or post-entry (but pre-integration) levels as in the case of fv-1 (Lilly, 1970
; Best et al., 1996
).
enJSRVs provide another example of retroviral interference, as one of the enJSRVs loci (enJS56A1) blocks exogenous JSRV viral particle formation late in the replication cycle at a post-integration step. As described above, enJS56A1 is unable to release viral particles in transfected cells but expresses abundant quantities of intracellular Gag (Palmarini et al., 2000b). Intriguingly, the defect in viral particle release possessed by enJS56A1 is trans-dominant over the capacity of JSRV to make viral particles (M. Mura & M. Palmarini, unpublished data). In particular, release of viral particles in the supernatant of 293T cells transfected with JSRV plasmid was inhibited if the cells were co-transfected with enJS56A1. The dominant negative activity shown by enJS56A1 is specific for ovine betaretroviruses. enJS56A1 inhibits JSRV particle release, but does not interfere with the exit of Moloney murine leukaemia virus (MMuLV) or MasonPfizer monkey virus (MPMV) (M. Mura & M. Palmarini, unpublished data). The biological significance of these data is enhanced by in vivo observations of enJSRVs Gag protein expression in the epithelium of the ovine uterus (see below; Palmarini et al., 2001a
).
An obvious possibility is that some enJSRV loci do not encode the so-called late (L) domains within their Gag protein whose disruption result in normal virus assembly, with the exception of particle release (Wills et al., 1994; Xiang et al., 1996
; Puffer et al., 1998
; Yasuda & Hunter, 1998
; Yuan et al., 1999
). L domains function by recruiting cellular factors such as Tsg101, Nedd4 and ESCRT-I and exploit the cellular endocytic trafficking machinery to release viral particles (Freed, 2002
). Classical L domains are present in the JSRV21 VR2, but these motifs are also conserved in the VR2 of enJS56A1. Analysis and functional characterization of enJSRVs might reveal novel retroviral late domains or even help to understand the mechanisms of exit from the cells of retroviral particles.
enJSRVs thus appear to block JSRV at two levels (Fig. 2). The first block acts at the level of virus entry by receptor interference while the second step blocks most likely viral particle transport or exit. This is a powerful example that supports the hypothesis that ERVs have protected their host against infection of related pathogenic retroviruses.
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Possible roles of enJSRVs in sheep reproductive biology
enJSRVs are highly expressed in the genital tract of the ewe. The localization, level and timing of expression of enJSRVs lend support to the hypothesis that these loci are important in female reproductive tract and placental biology. Indeed, expression of ERVs in the genital tract and placenta of various animal species has been described for at least three decades (Kalter et al., 1973, 1975
; Vernon et al., 1974
; Smith & Moore, 1988
; Harris, 1991
; DeHaven et al., 1998
).
Embryo development in sheep
In sheep, the ovulated oocyte is fertilized and develops into a morula embryo in the oviduct and then is transported from the oviduct into the uterus (Guillomot, 1995). Between Days 12 and 16, the conceptus rapidly elongates to a filamentous form that achieves contact with most of the luminal epithelial cells lining the uterine endometrium (Guillomot et al., 1981
). The morphological development of the sheep blastocyst from spherical, to tubular, to filamentous conceptus during the peri-implantation period coincides with the production of large amounts of interferon-tau (IFN-
) from the mononuclear trophectoderm (Spencer et al., 1996
; Bazer et al., 1997
; Spencer & Bazer, 2002
). These events ensure survival of the corpus luteum which produces progesterone, the hormone of pregnancy (Spencer et al., 1996
).
Implantation is initiated by the conceptus on Days 14 to 16 of pregnancy. As the blastocyst develops into an elongated conceptus, the outer trophectoderm transiently contacts uterine endometrial luminal epithelial cells in preparation for implantation (Guillomot et al., 1981; Guillomot, 1995
). Apposition of conceptus trophectoderm and endometrial luminal epithelium is initiated on Day 14, followed quickly by attachment on Day 15, and firm adhesion on Days 16 to 18 (Guillomot et al., 1981
). Between Days 15 and 16, the binucleate syncytiotrophoblast cells of the placenta differentiate from the mononuclear trophectoderm cells.
enJSRVs expression
enJSRVs are abundantly expressed in the epithelia of female reproductive tract tissues (Fig. 3) (Spencer et al., 1999
; Palmarini et al., 2000b
, 2001a
). This finding may reflect tropism for the female reproductive tract by an ancestral exogenous retrovirus that was the predecessor of enJSRVs. Using sensitive PCR analyses, enJSRVs RNA can be detected in a variety of tissues, including lungs, kidneys, thymus, bone marrow, spleen, mediastinal lymph nodes and leukocytes (Palmarini et al., 1996b
). However, the highest levels of enJSRVs RNA expression are observed in the female reproductive tract. In the uterus, abundant enJSRVs expression was observed solely in the endometrial luminal epithelium and glandular epithelium of the uterus (Spencer et al., 1999
; Palmarini et al., 2000b
, 2001a
).
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The increase in epithelial enJSRVs expression occurs during a period when the blastocyst hatches from the zona pellucida on Day 9, transitions from a spherical to tubular conceptus by Day 11, and then undergoes rapid elongation beginning on Day 12 to a filamentous conceptus that occupies the entire uterine horn by Day 16 (Guillomot et al., 1981; Guillomot, 1995
; Palmarini et al., 2001a
). These developmental changes in the conceptus involve rearrangement and proliferation of the mononuclear trophectoderm cells which produce IFN-
, a novel Type I IFN that is the pregnancy recognition signal (Spencer & Bazer, 2002
). The timing of enJSRVs expression is coincidental with the period of conceptus implantation. We hypothesize that an interaction between the enJSRVs Env (expressed in the uterine epithelium) and Hyal-2 (in the trophoblast) facilitates the process of conceptus implantation in the uterus.
enJSRVs are highly expressed in the placental binucleate cells
In the uteri of pregnant ewes, expression of enJSRVs is also observed in the developing placenta. This phenomenon is remarkably similar to the expression of HERV-W in the human placenta (Blond et al., 2000). The syncytiotrophoblast is the outer layer of the placenta that evolves from the mononuclear cytotrophoblast. In the ruminant placenta, the mononuclear cells of the trophoblast are the source of binucleate cells that arise from their cell duplication without subsequent division (Wooding, 1982
). Interestingly, we detected both enJSRVs RNA and immunoreactive proteins in the sheep placental binucleate cells (Fig. 4
) (Palmarini et al., 2001a
). The binucleate cells first develop in the placenta on Day 16 and continue to develop until Days 6080 when placentation and placentome formation is complete. The binucleate cells form the syncytiotrophoblast by fusing with the endometrial luminal epithelium in both caruncular and intercaruncular areas. The binucleate cells display invasive properties and they are abundantly present in the placentome. The placentomes are formed mainly by binucleate syncytiotrophoblast cells fused with the uterine endometrial luminal epithelium. The binucleate cells solely synthesize and secrete placental lactogen, a key hormone in pregnancy that stimulates endometrial gland morphogenesis and differentiated function for fetal nutrition (Spencer & Bazer, 2002
).
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The sheep model is thus uniquely suited to test the biological relevance of ERVs in placental morphogenesis given the ample similarities between enJSRVs and HERV-W and the impressive techniques available in sheep reproductive biology.
enJSRVs expression is regulated by progesterone in vitro and in vivo
In the ovine endometrium, the expression of enJSRVs RNA is correlated with circulating levels of progesterone and epithelial progesterone receptor (PR) expression, suggesting that the enJSRV LTR (or the LTR of some enJSRV loci), containing the viral promoter and enhancers, is influenced by progesterone. In transient transfection assays, the LTR of the enJS59A1 locus was transactivated almost 10-fold by progesterone, but the effects of progesterone on the LTRs of exogenous JSRV was minimal (Palmarini et al., 2000b). The LTR of the exogenous JSRV is activated by lung-specific transcription factors, such as HNF-3
(Palmarini et al., 2000a
; McGee-Estrada et al., 2002
), while the tested enJSRV LTRs are not affected by HNF-3
. These results support the hypothesis that the exogenous JSRV and ENTV developed their pulmonary tropism relatively recently and quite possibly after the integration of the enJSRV loci in the sheep germline.
Recent data indicate that enJSRVs expression is directly regulated by progesterone and progesterone receptor in the ovine endometrial epithelium also in vivo (K. E. D. Dunlap & T. E. Spencer, unpublished data). In situ hybridization analyses of uteri collected from sheep treated with progesterone and progesterone receptor antagonists showed a substantial reduction in enJSRVs expression. On the other hand, IFN- did not affect enJSRVs expression. These in vivo observations confirm those from in vitro experiments indicating that progesterone, acting through PR, increases expression of enJSRVs in the endometrial lumenal and glandular epithelia in a temporal manner coincident with the beginning of conceptus elongation and implantation.
Distribution of enJSRVs in Artiodactyla
Sheep have approximately 20 enJSRVs loci as determined by Southern blotting hybridization (Hecht et al., 1994, 1996
). Closely related viruses are found in goats (Capra hircus) in similar copy numbers as sheep; the goat hybridization pattern is different from sheep, but one that is generally conserved among goats and wild goats. However, the differences in restriction enzyme profiles between sheep and goat lineages suggest that much of the amplification from founding viruses within the respective genomes occurred after the divergence of goats and sheep approximately 410 million years ago (Irwin et al., 1991
; Miyamoto et al., 1993
; Honeycutt et al., 1995
; Reza Shariflou & Moran, 2000
).
Recent data indicate that two of the twenty enJSRVs loci have a conserved chromosomal location in sheep and goats mapping on chromosome 1 (1q45) and 2 (2q41) (Carlson et al., 2003). This observation strongly suggests that these two loci were fixed in the germline of a host that existed before the divergence of the genus Ovis from the genus Capra. Interestingly, one to three bands hybridizing at high stringency with JSRV probes were found in cattle and in some members of the Cervidae. The domestic cattle and deer diverged from the other ruminants between 18 to 19 million years ago. Artiodactyls that diverged much earlier, such as the domestic pig (55 millions years ago), do not show enJSRVs sequences by Southern blotting, although endogenous betaretrovirus sequences have been detected (Ericsson et al., 2001
). Strikingly, the more recently diverged species, such as sheep, goats and domestic cattle, have evolved an increased number of placentomes (Fig. 5
). The domestic pig has no placentomes, no binucleate cells and no syncytiotrophoblast. Therefore, it is plausible that integration of enJSRVs into the ruminant germline may have assisted the selective pressure towards the formation of placentomes and syncytiotrophoblast. However, by Southern blotting no JSRV-related bands were found in the DNA of Mountain goat (Oreamnos americanus) and this piece of data would be against the presence of some enJSRVs loci common to all ruminants (Hecht et al., 1996
). More hybridization studies are necessary to further investigate the distribution of enJSRVs in ruminants and artyodactyla by using probes derived from the more ancient enJSRV loci.
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The placenta has evolved repeatedly in different groups of organisms, including fish, amphibians, reptiles and mammals (Blackburn, 1999). A model of placental evolution can be derived from fish of the genus Poeciliopsis. These fish display variation in live-bearing embryos that range from species that maintain eggs after fertilization with no maternal provision to those that have various degrees of maternal provisioning after fertilization. The latter are associated with maternal and fetal membranes that are functionally similar to a mammalian placenta. Recent data indicate that placentas (or pseudo-placentas) in Poeciliopsis evolved independently multiple times in 750 000 years or less (Reznick et al., 2002
). This is the same time-scale suggested by theoretical calculations for the evolution of complex eyes.
Many viviparous species exhibit placentas or similar membranes to nourish embryo development. The placenta evolved concomitantly with viviparity, because thinning of the eggshell allowed for apposition of the extraembryonic membranes to the uterine lining. The evolutionary implications are remarkable. Given that viviparity has evolved on over 100 separate occasions among squamates, placental organs must have also originated as frequently (Blackburn, 1999). No other organ is known to have originated on so many occasions, and no other organ shows such wide structural variability. In Eutheria (e.g. all mammals with the exceptions of marsupial and monotremes), the wide differences among major taxa suggest a polyphyletic origin. Thus, ERVs might have played one or more major roles in placental morphogenesis but not necessarily in all the species. Given the structural diversity of placentas and their likely polyphyletic origin, a common ERV with a biological role in the reproductive biology of all Eutheria most likely does not exist.
enJSRVs expression in the ovine foetus
enJSRVs are highly expressed in the sheep fetus (Fig. 6) (Spencer et al., 2003
). Specific expression of enJSRVs RNA is observed in the lamina propria of the gut. Expression of enJSRV genes during fetal development may explain some aspects of the pathogenesis of the disease induced by the related exogenous JSRV after birth. Sheep affected by OPA or ENT do not develop circulating antibodies towards JSRV or ENTV (Sharp & Herring, 1983
; Ortin et al., 1998
). Indeed, expression of enJSRVs RNA is detected in Peyer's patches and thymus of fetal sheep (Spencer et al., 2003
). In particular, expression of enJSRVs in the thymus is detected predominantly in the cortico-medullary junction. The final selection of T cells occurs in this region of the thymus (Griebel, 1998
). These results support the hypothesis that sheep are tolerized towards the exogenous viruses by expression of enJSRVs in the fetus during development of the immune system. The observation that antibodies can be detected in sheep immunized with recombinant JSRV capsid or surface proteins in adjuvant (Sharp & DeMartini, 2003
) does not contrast with a possible enJSRVs-induced tolerance. All processes involving tolerance, both central and pheripheral, are recurring events and may be broken. Several reports in the litterature show that tolerance can be broken when self-antigens (especially in large amounts) are detected in the presence of pro-inflammatory signals (e.g. adjuvants) that promote the maturation of antigen-presenting cells (Burt et al., 2002
; Ohashi & DeFranco, 2002
).
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The expression of enJSRVs in the fetus also has implications for the design of strategies to control JSRV infection. OPA is one of the major infectious diseases of sheep. Given the extensive homology between JSRV and enJSRVs it is difficult to hypothesize a vaccine that can elicit a strong immune response in the sheep, as most viral epitopes would be recognized as self-antigens. Moreover, enJSRVs proteins are highly expressed in the sheep genital tract, and consequently even if a hypothetical effective JSRV vaccine was to be found this could have adverse effects on normal host cells. A critical evaluation of reproductive performances of sheep immunized with JSRV-based vaccines will have to be introduced in future safety and efficacy trials.
Conclusions
Many theories on the biological relevance of ERVs have been advanced during the last 20 years but few model systems have been investigated to substantiate experimentally these hypotheses. We speculate that enJSRVs were originally selected as they protected their host. enJSRV expression in the genital tract might have conferred an evolutionary advantage for sheep/goats through resistance to infection from related exogenous betaretroviruses circulating at that time. This could have provided a selection pressure for betaretroviruses with tropism towards the respiratory tract (e.g. JSRV and ENTV) rather than the genital tract (Fig. 7). Sheep betaretroviruses with tropism for the respiratory tract might have had a higher chance to establish a successful infection in a host with high-level expression of enJSRVs in the genital tract. Once fixed in the germline of the host, we speculate that enJSRVs expression favoured the process of conceptus implantation and influenced the placental morphogenesis of its host by contributing to the formation of the syncytiotrophoblast and of the placentomes of the ruminant placenta.
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ACKNOWLEDGEMENTS |
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