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Evolutionary Aspects of Human Endogenous Retroviral Sequences (HERVs) and Disease

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Endogenous retroviruses (ERVs) are remnants of retroviral infections. ERVs preserve functions of exogenous retroviruses to various extents. ERVs are both parasites and symbionts. Although the most pathogenic elements are eliminated by selection, some pathogenicity may remain. Some recently endogenized elements of mice and cats are known to cause disease. The situation in humans is less certain. Diseases where a role for ERVs has been discussed are multiple sclerosis, schizophrenia, diabetes, systemic lupus erythematosus, seminoma, malignant melanoma, preeclampsia and azoospermia. Several pathogenic mechanisms have been implicated: Antigenic mimicry, immune dysregulation, receptor interference, growth stimulation by cis- or transactivation, loss of physiological functions mediated by retroviral genes, and gene loss by illegitimate recombination are among them.

In most cases, much work remains before a pathogenic mechanism is established. The biology of HERVs must be better understood in order to understand their role in human disease.

Introduction

Virus-induced disease is a special case of the interaction between host and virus. An endogenous retrovirus (ERV) is part “virus”, part “selfish gene”(see below), part “host gene”, and part “sequence”. The least pretentious aspect is the last one. In order to avoid overinterpretation e will therefore in the following use the term “endogenous retroviral sequences” (ERVs). This term solely reflects the structural similarity between sequences of exogenous (infectious) retroviruses (XRVs) and ERVs. ERVs occur not only in all vertebrates1,2 but also the whole animal kingdom and in plants where they often are dominating genetic components. The interactions of ERVs with the host are manifold, and go beyond host-virus interactions as they are usually discussed. Endogenization of an XRV is an example of lateral gene transfer, and ERVs contribute in several ways to genetic diversity.3,4 In an evolutionary context, disease equates negative selection. As the persistence of ERVs in a lineage can stretch over several hundred million years there is ample time to establish a stable host-viral sequence interaction, with a minimum of negative selection, i.e., disease. A fundamental question therefore is: Do ERVs induce disease?

The question is justified because of its medical importance. In general, mobile genetic elements (like ERVs) mainly cause disease by transposition.5 It is a special case of genetic disease, i.e., disease arising from mutation in the host genome.

In a broad biological context, the answer is “yes, ERVs can cause disease”. In an intensely studied species, mice, recently integrated ERVs like the AKR murine leukemia virus, and intensely transposing ERVs like intracisternal type A particle sequences (IAPs), are major causes of disease (for a review see ref. 6). In the former case, production of infectious virus leads to transduction of oncogenes and immune deficiency. In both cases transposition can knock out important genes and/or activate oncogenes. Consequently, the expected selection neutrality of ERVs may take a rather long time to develop.

The “pacification” of a retroviral gene is not straightforward. Retroviruses carry with them a number of cis- and trans-acting mechanisms optimized to suit a free-living exogenous virus, making them potentially dangerous to the host even after eons, when the integrated viral gene (“provirus”, or “virogene”) has been severely damaged. Eukaryotic cells probably have been exposed to retroelements since their very beginning. More than half of the human genome has probably undergone reverse transcription before incorporation.3,7 Thus, many defence mechanisms against damage from newly acquired retroelements must exist. Some are known. Methylation8 and inhibitory RNA9 are two of them. Previous ERV integrations may protect against new ones in several ways.10 However, in principle there are two major causes of disease; either i. there are adverse environmental influences, i.e., a conflict of interest between an invading microbe and the host, occasionally being negative for the host, or ii. there are imperfections in the host machinery itself, such disease being of a degenerative or chance nature. The subject of this essay has elements of both. We will discuss disease from the aspect of the interplay between host and retrovirus as a price for the evolutionary flexibility provided by the ERV.

We will also give a brief review of the status of the HERV-disease field. The provisional hybrid HERV nomenclature proposed by Andersson et al11 will be used with slight modifications. Briefly, it is “HERV-X(clone or sequence name, group)”, where X is the tRNA specificity of the primer binding site, and group a cluster name based on sequence similarity, if defined. This nomenclature is an attempt to join the previous PBS-based nomenclature12 to a sequence similarity based one.13

Animal ERVs and Disease

The first findings were made in chicken, mice and cats. During the 1930's a factor was found in some inbred mice that could transmit breast cancer (Mouse Mammary Tumor virus, MMTV).14 It is now known to be a Betaretrovirus. During the 1970's it was shown that both MMTV and mouse leukemia virus (MLV; belonging to the Gammaretrovirus genus) exist both in infectious (exogenous) and hereditary (endogenous) forms. The former is contagious between individuals in the same generation (horizontal spread), the latter between subsequent generations (vertical spread). The pathogenic role of ERVs can be elaborate. In MLV leukemogenesis there is a stepwise sequence of recombinations with ERVs leading to the pathogenic virus.6 In both the MMTV and MLV examples ERV expression is positively correlated with disease.

The disease in mice from Lake Casitas in California is another example. These wild mice consist of two populations.15 One population gets a degenerative neurological disease, a myelitis. It is caused by a pathogenic variant of MLV. After infection early after birth, the infection becomes chronic, with viremia for several months. The other mouse population is resistant against the disease. The resistant mice have a genetic property (FV4), which is a defective endogenous MLV sequence. This apathogenic ERV produces an envelope glycoprotein which protects against the exogenous virus by binding to and blocking the same cell surface receptor that is used by the pathogenic exogenous MLV. The example shows i. that infection just after birth followed by a chronic viremia eventually can lead to disease, and ii. that an endogenous retroviral sequence can protect against an exogenous retrovirus. In this case ERV expression is negatively correlated with disease. The epidemiology of the disease is determined both by heredity and infection after contact between individuals (environment).

Events following Endogenization of a Retrovirus

As seen in Figure 1, ERVs seem to undergo a more or less regular sequence of events. Initially, the provirus is a "selfish" gene,16 i.e., it is optimising towards its own replication and replicates like an exogenous retrovirus in somatic cells, occasionally infecting other individuals, being more or less damaging to the host. In order to become an ERV, a retrovirus must infect a germ line cell. That cell must survive. It must give rise to offspring which is unhindered to reproduce. Already at this stage, harmless ERVs are selected. For example, endogenous replication competent HIV would be incompatible with life.17 After a subsequent long period, the ERV may or may not be fixed in the species. This filters away most integrations, especially those with pathogenic properties. However, a population will never reach complete genetic equilibrium. Due to the evolution of both organism and its environment, the genome is in continuous transition, demanding genetic flexibility. Retroelements are prime providers of genetic flexibility, which gives a certain positive selection value to them. Therefore, rare cases of ERV pathogenicity will not be eliminated.

Figure 1. Events following endogenization of a retrovirus.

Figure 1

Events following endogenization of a retrovirus.

After an initial integration there may be intense reintegration into somatic cells, occasionally spilling over into the germ line. Within a short time, many follow-up integrations can accumulate in the germ line. Each integration may create havoc through the long range effects of retroviral enhancers.18 This may reduce host fitness, encouraging crippling of the provirus(es), especially their LTRs. The initial pathology is centered around retroviral effects at the cellular or organismic levels, like those of an exogenous retrovirus.

Directly after integration and until severely mutated, ERVs may also serve as hotspots for gene loss through illegitimate homologous recombination, causing genetic disease (see below).

Initial beneficial effects of ERVs may be protection from XRVs by receptor interference (FV4),6 or interference with formation of the preintegration complex (FV1).19 Later, ERVs may become physiological servants to the organism. These events are briefly mentioned in Figures 1 and 2. Potentially useful functional modules offered by retroviruses are tissue specific enhancers,20,21 polymerase II promoters,22 splice donors,23 splice acceptors,24 a myristoylated cytoplasmic membrane protein,25 structural and nucleic acid binding proteins capable of packaging RNA, a dUTPase,26 a protease,27,28 an RNA dependent DNA polymerase with RNAse H29,30 (reverse transcriptase may also be involved in the pathogenesis of nonretroviral RNA viruses due to their persistence as DNA copies31), an integrase,32 an envelope protein which binds to a host surface protein, a spring-loaded transmembrane protein ready to fuse membranes and possibly cause immunosuppression, and a polyadenylation signal and site.33-35 Retroviral single LTRs are very abundant36 and probably have a great influence on the expression of many nonretroviral human genes. Several cloned HERV enzymes: protease,27,28 dUTPase,26 reverse transcriptase29 and integrase32 have shown function. So far, they all derive from the HERV-K(HML-2) group. The most likely scenario for such a function added relatively late during evolution is modulation of existing cellular mechanisms.

Figure 2. Activation of an ERV through mutation.

Figure 2

Activation of an ERV through mutation.

Even old retroviral integrations retain a part of their retroviral properties, which makes them “genetic jokers”, a little less predictable than other portions of the genome. The silencing of ERVs may therefore be more eventful than the silencing of other genes. The sophisticated regulatory machinery of a retrovirus involves a careful balance of positive and negative regulatory functions, and interaction between structural proteins (Fig. 2). During the gradual mutational crippling of ERVs opportunities for deregulation occur, i.e., a deleted splice acceptor leads to splicing into downstream host genes.37 HERV proviruses can also downregulate translation of a nearby host gene, presumably through strong secondary structure.38,39 Thus, a price to be paid for the genetic flexibility provided by ERVs is a small pathogenic potential remaining even after many millions of years.

Factors which may prolong the activity of ERVs despite stop or frame shift mutations are i. copackaging of defective RNAs into particles encoded by other ERVs, ii. complementation of proteins from related elements which still have an active protein, iii. recreation of functional hybrid genomes by gene conversion40,41 (see below) or recombination, iv. evasion from the nonsense mediated decay system42,43 (Fig. 3), v. stop codon suppression like selenocysteine readthrough of TGA (“Opal”) stops. 44 Although the latter mechanism has not been demonstrated for HERVs, it potentially could prolong their activity. The validity of point i. was recently emphasized by a demonstration of pseudotyping of HIV capsids into HERV-W Env ex vivo, allowing HIV access to a new set of target cells.45

Figure 3. Removal of unspliced genomic retroviral mRNA from the mainstream of mRNA processing.

Figure 3

Removal of unspliced genomic retroviral mRNA from the mainstream of mRNA processing. The bulk of all cellular mRNAs are processed after translational proofreading in the nucleus. mRNA containing premature stop codons is then degraded in the cytoplasm (more...)

Many transcribed genes are reintegrated as processed pseudogenes through the LINE1 reverse transcription/integration mechanism. Evidently, some of the HERV integrations arose in this way.49 It provides a pathway for intragenomic spread of defective elements.

Examples of events which resulted in a physiological interplay between HERVs and other genes have been found in genes involved in energy metabolism: transaldolase (which contains the repetitive element HRES-1 which has a weak similarity with retroviral sequences),50 apoC-I lipoprotein,22 leptin receptor,51 leptin itself,52 alcohol dehydrogenase,53 and amylase.20 However, no metabolic diseases due to lack of HERV function have yet been described.

A good illustration of how an ERV can modify function in a complex regulatory situation is the beta globin locus of primates.54,55 An ERV-9 LTR integrated in the locus control region and assumed transcriptional control, i.e., beta globin transcripts initiate from the ERV-9 LTR promoter. It thereby shunted out several other promoters within the locus control region. These promoters remain cryptic, and can regain control if the ERV-9 LTR is experimentally damaged. It is surprising that the acquisition of a new retroviral promoter, with all its retrovirus-specific transcription factor binding sites, was compatible with function in the beta globin locus.

Active HERVs, Expressed As Particles or As Proteins

HERVs which retain the ability to produce particles and proteins can be referred to as "active". Like the pathogenic animal ERVs they often are relatively recently endogenized. In principle, particle production may or may not be accompanied by transposition. Judging from the experience from animal ERVs, active HERVs are more likely to cause disease than more defective HERVs.

HERV Polymorphism

In animals, a major cause of retrovirus-induced disease is reintegration (transposition). Unlike the LINE elements, transpositional activity of HERVs has not been directly demonstrated. However, if HERVs are integrationally active, integrational polymorphism should exist in the population. Several human-specific integrations of HERV-K(HML-2) was described,56-58 highlighting them as recently acquired and as candidates for integrational polymorphism. It was therefore logical when the group of Jack Lenz recently described two cases of HERV-K(HML-2) integrational polymorphism.59 The proviruses (HERV-K(113,HML-2) and HERV-K(115,HML-2) ) seemingly are intact, for the first time providing HERV candidates with potential infectivity. Using differential amplification techniques, several new unique HML-2 cluster 9 integrations60 were detected. The presence of integrational polymorphism raises the possibility of active replication of HERV-K(cluster 9, HML-2), in somatic cells. If so, overt pathogenicity due to viral growth and even insertional oncogene activation may occur. The disease association of cluster 9 should be further investigated.

The occurrence of human-specific integrations in other HERV groups has not been systematically investigated. There is however one in the HML-4 group (LTR13).61,62

Another kind of HERV integrational polymorphism is seen in the MHC region.63-66 It is likely that the HERV diversity in this region mostly is produced by HERVs being coselected as parts of cassettes, in linkage with actively selected MHC genes.67 HERVs, like other repetitive elements, can give rise to illegitimate homologous recombination (see below). This has been observed in the MHC region.68

Single nucleotide polymorphism (SNP) also occurs in HERVs.69-71 This is to be expected from genes who mostly mutate at a “pseudogene” rate.72

Retroviruslike Particles

Retroviruslike particles are normally formed in placenta of many animals.73-79 This is true also for humans80 and also occurs in human teratocarcinoma cell lines81 and in a breast cancer cell line (see below).82,83 HERV-K(HML-2) genomes are major components of those particles. For the purpose of this review we will use the following distinctions: A “particle” is an entity which can be spun down at 100 000 × g. If the particle is filterable through 0.2 μ filters, bands at a density of 1.16 g/cm3 in a sucrose density gradient, or at a corresponding density in another medium, and contains retroviral RNA and/or reverse transcriptase, it is a “retroviral particle”. Other important but not obligate criteria are electron microscopy, which reveals the morphology, and antigenicity, which may reveal the source of the capsid or envelope proteins. The term "retroviruslike particle" is justified if most but not all of these properties are demonstrated.

Besides the retroviral particles mentioned above, retroviral particles are produced by the human breast cancer cell line T47D.83 These particles contain RNA from HERV-K(T47D,HML-4), HERV-P(T47D) and HERV-K(HML-6). Retroviruslike particles have been found in human serum and cerebrospinal fluid84-88 (see also below, Figs. 4, 6 and 8). An important aspect of retroviral particle detection by reverse transcription PCR (RT-PCR) is sensitivity and specificity. Although excellent as discovery tools in an initial phase, broadly amplifying systems like the PAN primers,89 or MOP primers90 tend to have a good specificity but a relatively low sensitivity. They are also very sensitive to mutations in the primer target sequences, which can lead to an uneven representation of intended targets among the amplimers. In the context of this review, it is especially interesting that the PAN primer system can probably not amplify many HERV-H sequences due to variation in the LPQG and YXDD motifs (Blomberg, unpublished). Thus, such studies should be followed up with studies using other RT-PCR systems, hybridisation microarrays, or cDNA libraries.

Figure 4. ERV sequences found as RNA in particles.

Figure 4

ERV sequences found as RNA in particles. Human ERVs are denoted HERV-X, hml-x, ERV3, ERV-FRD or ERV-FTD. Literature references are given in the text. The neighbour-joining tree tree was constructed from an alignment of 900 base pairs from the amino terminus (more...)

Figure 6. Connection of retroviruses to human disease.

Figure 6

Connection of retroviruses to human disease. In cases where causality is not established the disease name is shown with a question mark. Details are given in the text.

Figure 8. Characterisation of retrovirus secreted from B cell lines isolated from two MS patients.

Figure 8

Characterisation of retrovirus secreted from B cell lines isolated from two MS patients. Modified from Moller-Larsen et al.

Figure 5. ERVs with ORFs.

Figure 5

ERVs with ORFs. ERV sequences known to have at least one ORF in gag-pro-pol or env genes are symbolised with a sun. References: HERV-H env ORF (Lindeskog et al. 1999, de Parseval et al. 2001, Jern et al. 2002),,, HML-2 gag, pol and env ORFs (Mayer et (more...)

Particles from the latter sources (serum and cerebrospinal fluid), and from B cells of MS patients, have been reported to contain nucleic acid from several HERVs, notably HERV-H and HERV-W.84, 86 Although it has not been systematically investigated, many of the RNAs encapsidated in the particles from these sources have been defective. They may have been cross-packaged into particles encoded by one or several HERVs which have non-defective capsid or envelope genes.

“Infectious” HERVs, meaning passage of HERV production in cell culture, have been reported by three groups.86, 88, 97, 98 These "isolations" of infectious HERVs were done with samples containing particles with HERV-H or HERV-W sequences, respectively. Both of these class I HERVs have members with ORFs in env and relatively intact gag and pol frames. Because human target cells usually contain the same DNA sequence as the RNA in the particles, a passage into cell lines without corresponding HERVs is required to definitely ascertain the isolation. Such experiments have been initiated99 (see below). Another requirement is that the produced particle-associated sequence should be virtually identical to the sequence in the input particles. These basic criteria have not been met. Much work is required before the infectiosity of the particles can be considered established. However, if the reports are right, a paradigm shift may be on its way. The possibility that such viruses are "breakout viruses" (see below and Fig. 7) should be addressed.

Figure 7. Generation of “Breakout” exogenous retrovirus from a proviral quasispecies of endogenous retroviral sequences.

Figure 7

Generation of “Breakout” exogenous retrovirus from a proviral quasispecies of endogenous retroviral sequences. Defects in the original proviruses are depicted with an X. This is a hypothetical scheme which, however, has support from animal (more...)

Intraindividual ERV Evolution,“ERV Breakout”

The thousands of ERV integrations can be viewed as a “proviral quasispecies” analogous to the quasispecies of XRVs. This genomic quasispecies is not static. From time to time it is modified by gene conversion, which pastes one sequence over a highly similar one.40,41, 94 Therefore the stops and frameshifts will vary from cell to cell and from individual to individual. In this ERV lottery, ORFs can both be obliterated and recreated. The extent of this type of somatic variation in humans is not known, but several observations indicate that it is not uncommon.40,94 Although many retrotransposons become epigenetically silenced, often by methylation,8 their degree of methylation varies, and is diminished during aging.100,101 Indeed, the expression of endogenous retroviruses in mice is age-dependent.102-106 Besides variation in methylation, there is evidence for a second mechanism of ERV activation. We would like to call it “ERV breakout” (Fig. 7). Starting from humble beginnings, maybe after a temporary demethylation,101 one quasispecies member (B) may provide functional capsids and partially functional enzymes. Another quasispecies member (A) may provide the envelope proteins. It is conceivable that such particles can copackage RNAs from each other and other more or less defective members of the quasispecies (Fig. 7), which during reverse transcription recombine, infect with a low efficiency and reintegrate. Once the process starts, it is self optimizing, and may generate a more or less infectious exogenous retrovirus, in some cases progressing to a replicatory avalanche. This is reminiscent of the self optimizing nature of tumour cells, once they start to escape from extraneous control of cell division. The process will be more rapid the more replication competent the starting provirus is. A “breakout” process involving both mutation and recombination occurs regularly in AKR mice during leukemogenesis.6,106 A related phenomenon is the so-called “patch repair” of MLV.107 ERV breakout to XRV could be a common phenomenon in many species, restarting early, maybe after the conception of an individual, becoming more or less developed during its lifetime. A number of factors will be influential: initial presence of intact or nearly intact ERVs, the often restricted cross-packaging of defective ERV RNA,108,109 the extent of mRNA degradation due to the nonsense mutation decay mechanism,42,43 and the degree of ERV RNA and protein expression. A breakout XRV then could be pathogenic or not depending on its emergent properties. We suggest that this mechanism should be further studied in animal models and be addressed in studies on ERV pathogenesis in humans. It can be falsified by studies on substitutions and recombinations in viral particles, comparing the sequences of particle-associated RNA with that of related loci in genomic DNA.

Diseases Where a Connection with HERVs Has Been Implicated

Neurological Diseases: MS and Schizophrenia

The rapid and recent development of higher mental activity is a unique human event which probably required genetic flexibility and preparedness. Mobile genetic elements could therefore be suspected to have assisted in brain development.110,111 A connection between axon growth and retrotransposon transcription in the developing Drosophila brain has been described.112 Theoretically, remaining transposon activity could then be associated with disease.113 The upcoming comparison of chimpanzee and human genomes will shed light on this issue.114 Whether related to this or not, the neurological diseases MS and schizophrenia belong to the diseases where an increased production of retroviruslike particles and RNA have been reported (Figs. 3, 6 and 8).

In MS patients, particles containing reverse transcriptase were discovered at the end of the 1980's by a French and a Danish group in supernatants from cultured leptomeningeal and B cells from MS patients.84-87,115,116 Two main groups of particle-bound sequences have been detected. One belongs to the group HERV-W (see above, Figs. 4, 6 and 8), and was initially called "Multiple Sclerosis Retrovirus" (MSRV).84 The other belongs to the group HERV-H (see above, and Figs. 4, 6 and 8).86

Studying supernatants from two choroid plexus-derived cells and one B cell line, all three from MS patients, the French group found particles banding at 1.14-1.20 g/cm3 in sucrose density gradients which had reverse transcriptase activity and had an RNA from which a retroviral pol stretch was amplifiable with a broad RT-PCR (Fig. 8a). The sequence was similar to the earlier published ERV-9 sequence,117 and was fully sequenced by a primer walking procedure. It was initially called MSRV, later HERV-W. Using a HERV-W specific PCR, HERV-W RNA was detected in cell pellets of 5 of 10 cerebrospinal fluid (CSF) samples, while none of 10 CSF cell pellets from patients with other neurological diseases were positive. All of the five HERV-W RNA positive patients were not treated with immunosuppression. In a further study, using a nested RT-PCR approach targeted to the MSRV pol sequence,84 9 of 17 MS patients were positive for particle-bound HERV-W RNA in serum. Three of 44 controls were MSRV positive. A tendency towards a lower percentage of positivity in azathioprin/corticosteroid-treated persons was noted. A small Swedish study showed one MS patient with a variant of HERV-W RNA in serum,118 out of nine analysed, while none of 21 blood donor controls were positive. The broadly amplifying PAN primer system was used.89

The Danish group found RT-associated particles in supernatants of B cell lines from 5 of 21 MS patients, and from 1 of 13 healthy controls.119 Cultures which produced retrovirus-like particles also produced Epstein-Barr virus. The retrovirus-like particles had a type-C morphology, and banded at a density of 1.25 g/cm3. HTLV-1 banded in a similar fashion (Fig. 8b).120 Primers based on HERV-H clone RGH2 amplified HERV-H sequences from retroviral particles of supernatants from B cells of MS patients. They also amplified such sequences from particles in plasma of MS patients. Twenty four of 33 cell free plasma samples from MS patients were positive in the HERV-H PCR, whereas none of 29 plasmas from patients with other autoimmune disease and none of 20 plasmas of healthy controls were positive. Cloned amplimers from particles of four patients (two from B-cell supernatants and two from plasma samples) gave different sequences, but were still highly related to RGH-2. Thus, several HERV-H integrations may be involved. The nested HERV-W specific primer sets ST-1/2 did not amplify from the same particle preparations.

The occurrence of retroviral particles either containing HERV-H or HERV-W sequences is perplexing. However, the French group also found ERV-9 sequences in a minority of their particles. Both groups report heterogeneous sequences, i.e., more than one HERV-H, HERV-W and ERV-9 integration seem to contribute. A simple explanation is that several gammaretroviral HERV loci are activated in MS. Then the amplification specificity of the PCRs involved could favour either HERV-H or HERV-W/ERV-9 detection. This should be studied systematically with quantitative PCRs and sequencing of particle-bound RNA (Table 1).

Table 1. Models for a possible involvement of ERVs in MS and schizophrenia.

Table 1

Models for a possible involvement of ERVs in MS and schizophrenia.

The packaging of these RNAs is also astonishing. Although no candidate gag-pol HERV-H/W ORF is known (J Blomberg, unpublished observation) it is possible that such a protein can be created via somatic mutation (see “breakout RVs”, above), and provide the capsids. The envelope protein may be supplied via one or several of the known env ORF genes.71,93,121

Both the Danish and the French groups maintain that they can grow the respective virus in human cells97,98,116 (see the discussion on "infectious" HERVs). Considering the great number of microbes which have been associated with MS during the previous century these reports must be interpreted cautiously. However, the lead seems strong enough to motivate a thorough investigation.

A selective increase in HERV-W RNA expression was discovered by representational difference analysis (RDA) of monozygotic twin pairs discordant for schizophrenia in schizophrenic patients compared to those of mentally healthy controls.122 Particles containing RNA from HERV-W-like retroviruses have also been detected in cerebrospinal fluid of newly debuted patients with schizophrenia.88,99 However, also particles with RNA from related HERVs (i.e., ERV-9 and ERV-FRD, also known as HERV-P(T47D)) were detected. Ten of 35 newly debuted schizophrenia patients had HERV Class I RNA containing particles in CSF. Seven of the 10 had HERV-W, two had ERV-9 and one had ERV-FRD RNA. CSF from one of 20 patients with chronic schizophrenia, none of 22 patients suffering from non-schizophrenic neurological disease, and none of the healthy controls had particles containing HERV RNA. The PAN primer system89 was used. Some of the patients also had retroviral RNA in serum. The full spectrum of gammaretroviral RNA sequence containing particles in CSF and serum from MS and schizophrenic patients as well as in controls has not been determined. It would be interesting to know which loci and alleles that transcribed the RNA that got packaged into particles in MS and schizophrenia. It is appropriate to mention that HERV-W uses the glutamate transporter protein as a receptor.123 Glutamate is an important brain signal molecule of relevance for schizophrenia.124

Also in schizophrenia there are reports of virus passage.88,99 A particular strength of this claim is that owl monkey kidney cells were used. The owl monkey is a New World monkey, who does not have many of the more recent HERVs.

It is too early to judge whether the increased amount of HERV particles and HERV RNA in multiple sclerosis and schizophrenia is an epiphenomenon or a sign of a pathogenic role of certain gammaretroviral (Class I) HERVs. There is evidence (sometimes conflicting) that antigenic mimicry between brain proteins and antigens from some viruses elicits anti-brain autoimmunity in postinfectious encephalitides.125-128 Theoretically, a similar mechanism could operate in MS (see Table 1). However, mouse and rat ERVs can be activated nonspecifically, for example by anoxia.129,130 Recent publications131,132 have claimed that HERV-H and HERV-W transcription is upregulated in macrophages at the site of inflammation in MS brains. Thus, the occurrence of these RNAs and particles containing them in MS would just be a sign of immune activation. However, this does not explain the activation of HERV-W in schizophrenia, a disease without CNS inflammation.

How Could ERVs Cause MS and Schizophrenia? Theoretical Possibilities

Although MS and schizophrenia133 are two distinct diseases both tend to debut in 18—28-year-old persons. In both there is support both for genetic134 and for environmental, unevenly distributed, possibly infectious, etiological factors.135,136 Schizophrenia debuts often are seasonal.137 This is not an argument for a pathogenic role of HERVs which are present since conception in nearly all persons. The reasons for seasonality in viral infections are not entirely known. This epidemiological pattern is primarily connected with fecal-oral or airborne transmission. Such types of transmission are remote from currently known HERV biology. If HERVs, via a polymorphism or a reintegration event, would be the major etiological factors of MS and schizophrenia there should be a pronounced hereditary component and a minor environmental one. However, if HERVs modulate the disease by interaction with environmental factors, there could be equally important hereditary and environmental components of the etiology. The latter pattern is found in the neurological disease of Lake Casitas mice,15 where a defective ERV prevents infection from a pathogenic XRV by receptor interference. XRVs tend to behave in three fashions; I. as sexually transmitted infections, ii. as blood borne diseases or iii. as nonseasonal childhood infections. The debut age and seasonality pattern therefore do not fit entirely with the Lake Casitas model either. However, a common infection, which mainly infects during childhood, when it is rather asymptomatic, but is symptomatic (mononucleosis; "kissing disease") when infecting teenagers, is Epstein-Barr virus. A combination of a host factor (age) and salivary transmission of an infectious agent (EBV) is necessary to cause disease. The debut ages of both schizophrenia and multiple sclerosis agree approximately with the mononucleosis pattern. A similar reasoning was published early by Danish authors, who indeed have implied a role for EBV in MS.115,138 Another reason for a retarded appearance of disease caused by retroviruses is a persistent virus production with random integration, which eventually may cause neoplasia due to activation of a proto-oncogene.6 In this type of pathogenesis, various neoplasms, primarily leukemia/lymphoma, are the main outcomes. Neither MS nor schizophrenia are associated with such neoplasms. A third retroviral pathogenic mechanism is recombination between exogenous and endogenous retroviruses.6 Such recombinant viruses have new properties, some being pathogenic due to a large virus production and/or access to a new target cell. The immunosuppression which occurs in FeLV viremic cats may be of this kind.139 A common retrovirus (a “breakout” ERV or XRV) with limited replicatory potential theoretically could undergo recombination with a low frequency, or gradually mutate back to greater replicatory potential, causing disease in a few despite of ubiquity. These hypotheses are to some degree testable (Table 1).

As seen from this speculative reasoning, the explanation will not be straightforward. As a starting point, the frequency and amount of retroviral particles in body fluids of these patients and controls must be unequivocally established before a role for HERVs in these diseases can be inferred.

The HERV-Cancer Connection

There are many ways in which HERVs may be involved in normal and malignant growth. A striking dependence of a choriocarcinoma cell line on HERV-E expression for growth was elegantly shown143 (Fig. 9). Most probably, this occurs through HERV-E.PTN driven expression of the growth stimulatory factor pleiotrophin. If human choriocarcinomas in general have the same dependence, preventing HERV-E.PTN expression could be a useful target for gene therapy.

Figure 9. Effect of the depletion of HERV-E.

Figure 9

Effect of the depletion of HERV-E.PTN mRNA from JEG-3 choriocarcinoma cells. (A) Northern blot analysis of total RNA from control JEG-3 cells (lane 1) and JEG-3 cells expressing a ribozyme targeted to pleiotrophin mRNA (lane 2) is shown. (B) Proliferation (more...)

In animals, retroviruses and ERVs are known to be involved in carcinogenesis. The most well-known examples are leukemia caused by the ecotropic gammaretrovirus murine leukemia virus in AKR mice and the mammary tumours caused by the betaretrovirus endogenous mouse mammary tumour virus in GR mice, which primarily act by insertional enhancement of protooncogene promoters. These ERVs are intact and can produce infectious virus. Although a few HERVs seem to be intact, none of them are yet known to produce infectious virus. The class II HERV sequences are relatively closely related to MMTV and it has therefore been natural to look for expression of such viral sequences in human breast cancer. There are, however, no clear signs of a causal relationship between HERV class II and breast cancer,144,145 but there are a few reports on expression of HERV-K(HML-2) like RNA in leukemic leukocytes.146-148 Those reports need to be confirmed and extended. In the following we discuss some specific examples of possible involvement of HERVs in carcinogenesis.

Germ Cell (GC) Tumours, in Particular Seminomas

Even if HERVs are a type of transposons, stimulation via HERV integration close to a proto-oncogene has yet to be observed. This is in contrast to other retrotransposons, primarily the LINE1 elements, where several such cases have been discovered.5 However, there is a correlation between occurrence of antibodies to HERV in seminomas, a type of testicular carcinoma. During active disease, high titers of antibodies binding to several HERV-K(HML-2) proteins (Env and Gag) occur (Fig. 10 A and B). These antibodies disappear after treatment.149,150 Immuno EM confirms that anti-HERV particle (from teratocarcinoma cells) antibodies occur in GC tumours of males.151

Figure 10. A) Distribution of IgG antibody reactivity in the immunofluorescence test, using recombinant HERV-K(HML-2) Gag protein in a baculovirus system.

Figure 10

A) Distribution of IgG antibody reactivity in the immunofluorescence test, using recombinant HERV-K(HML-2) Gag protein in a baculovirus system.B) Prevalence of IgG antibody reactivity in the immunofluorescence (IF) test, using recombinant HERV-K(HML-2) (more...)

HERV-K(HML-2) virus is expressed in teratocarcinoma cell lines.81,153 HERV-K(HML-2) transcripts and proteins are also abundant in testicular and ovarian GC tumours except for teratomas and spermatogenic seminomas.154 HERV-K(HML-2) Gag proteins are also expressed in testicular and ovarian GC tumours.155,156 Human teratocarcinoma derived virus, HTDV, is a term coined after the demonstration of particles containing HERV-K10-like RNA,81 and Gag proteins antigenically related to HERV-K10 Gag in supernatant from a teratocarcinoma cell line.153 Although HTDV is not derived as a specific clone, this virus will here be referred to as HERV-K(HTDV,HML-2). Thus, the presence of both virus expression in GC cells and antiretroviral antibodies in male patients with GC tumours indicate a connection, etiological or not, with HERV-K(HTDV, HML-2). The most likely loci for production of HERV-K(HTDV, HML-2) particles are either HERV-K(113, HML-2) on chromosome 19p13 or HERV-K(HML-2.HOM), (here called HERV-K(HOM,HML-2)) on chromosome 7.

Although an oncogenic mechanism is not known, the research groups in Homburg and Langen focus on two novel HML-2 proteins, which arise by alternative splicing, i. rec, earlier called c-orf81,157,158 and, ii. np9159 (Fig. 11). HERV-K(HML-2) rec transforms cultured cells to grow as tumours in nude mice. It binds to a Zn finger gene, PLZF.160 PLZF is associated with retinoic-acid resistant forms of promyelocytic leukemia (PML). Hypothetically, PLZF acts via cyclin A2, a regulator of meiosis, which precedes formation of spermatozoa. Increased expression of rec indirectly could influence the maturation of GC to spermatozoa, and increase the likelihood of malignant transformation.160 The np9 protein is a newly discovered alternative splice product of HERV-K(HML-2)159 (Fig. 11). It is a nuclear protein which is expressed in GC tumours. Its oncogenic role in GC tumours is not defined.

Figure 11. Two types of HERV-K(HML-2) and their spliced mRNA transcripts.

Figure 11

Two types of HERV-K(HML-2) and their spliced mRNA transcripts. In addition to full-length mRNA and env mRNA, HERV-K(HML-2) type 2 produce rec (c-ORF ) as a product of splicing and frameshift from ORF-1 to ORF-2 (numbers over mRNA). HERV-K(HML-2) type (more...)

Among the candidates for a HERV-cancer connection, seminomas are the strongest. Even in this case, much work remains before an etiological connection can be considered as established.

A Malignancy-Associated Genotype of Some Betaretroviruses

The most common function of the env SU is binding of a receptor.161 Even though SU is a highly variable sequence, a conserved region in the N-terminal has been shown144 (Fig. 12). According to one research group this region encodes a putative Vβ7 T cell receptor specific superantigen, pSAG, as a product of HERV-K18, here called HERV-K (IDDM, HML-2).162 The conserved motif is also present in HERV-K(HOM,HML-2), discussed above, and in the Jaagsiekte sheep retrovirus (JSRV). JSRV is a contagious, possibly airborne, retrovirus which causes lung cancer in sheep.163,164 The tumorigenesis may be mediated through a) cell surface interaction with the tumor suppressor HYAL2, which is a receptor for JSRV in the bronchi,165 and b) participation in an intracellular tyrosine kinase signal cascade leading to growth stimulation.166 Endogenous JSRV variants do not have the tyrosine crucial for this pathway. JSRV is rather closely related to class II (genus betaretrovirus) HERVs (Fig. 4). The striking conservation in the amino-terminal portion of Env of class II HERVs and JSRV indicates that they may have the same receptor, i.e., HYAL2 (Fig. 12). Thus, there is reason to investigate if Env proteins of betaretroviral HERVs have any of these properties. Whether the growth modulating properties of this group of betaretroviral envelope proteins are related to its reported superantigen properties is obscure (see below). It is reasonable to assume that the original viruses which became HERV-K(HML-X) had some properties in common with JSRV.

Figure 12. Schematic structure of a subset of betaretrovirus Env proteins with a conserved motif in the N-terminus of SU.

Figure 12

Schematic structure of a subset of betaretrovirus Env proteins with a conserved motif in the N-terminus of SU.

Evasion of Antitumor Cytotoxicity Mediated via Gammaretroviral Transmembrane Protein

p15E is the transmembrane protein of feline leukemia virus (FeLV). The “p15E story” dates back to early work on FeLV pathogenesis and functions of retroviral proteins.167-170 The following effects were reported: i. an immunosuppressive effect of the transmembrane proteins of many (but not all) gammaretroviral transmembrane proteins and peptides derived (e.g CKS-17, consisting of 17 conserved amino acids) from the so-called immunosuppressive domain (ISU)170 (Fig. 13), ii. an increased expression of p15E-like epitopes in animal and human tumours as defined by monoclonal antibodies to p15E,171-173 which may be a sign of retrovirus-assisted evasion of anti-tumour cytotoxicity. Since then, “p15E” became a sometimes uncritically used catchword. Direct evidence for such a mechanism has however been published by the group of Heidmann.174,175 The p15E expression in some mouse and rat tumours has been reported by several authors.173,176 Whether a p15E mediated escape from tumour immunity is common in mice is less certain.176 Although a detailed appraisal of the p15E effect177,178 is outside the scope of this review, ISU peptides from p15E may inhibit protein kinase C,179,180 and binding of TGFβ to its receptor.181

Figure 13. Schematic view of an endogenous gammaretrovirus with its envelope (env) gene.

Figure 13

Schematic view of an endogenous gammaretrovirus with its envelope (env) gene. The immunosuppressive unit (ISU) in envTM containing the 17 amino acids long conserved CKS17 motif, is highlighted.

The first molecular evidence for the presence of p15E-like sequences in the human genome was published by Lindeskog et al182 The human genome contains a few HERV env sequences with open reading frame which are candidates for formation of a functional p15E-like human protein.71,93,183 The data on expression of p15E-like epitopes in human tumours are not as extensive as in animals. They are mostly based on immunofluorescence (IF) or RNA data. Foulds et al found p15E expression in 24 of 30 colorectal carcinomas and 4 of 4 gastric carcinomas.184 However, the molecular nature of the p15E like RNA detected in this work is obscure.

Sera from patients with head and neck carcinomas have been shown to contain p15E-like low molecular weight factors that inhibit the response of monocytes and macrophages to chemotaxis and that the bioactivity of these factors decreased to normal values after removal of the tumour.171 IFNγ is generally known to activate NK cells, but the subtype IFNγJ blocks this activation and thereby the NK-cells from boosting other IFN• subtypes.185 Anti-retroviral p15E antibodies decrease these immunosuppressive activities of IFN• suggesting a relationship between p15E-like factors and human IFN•.172 There is also a weak structural similarity between IFN• and p15E.172

In conclusion, there are interesting lead observations on a possible p15E mediated tumour evasion mechanism in humans, but much work on the signaling pathway of immunosuppression via TM-ISU and the frequency of TM-ISU mediated evasion from antitumour cytotoxicity, in humans and other animals, remains. More precise measurements regarding TM-ISU expression at the RNA and protein levels are also needed.

HERV-Encoded Tumor Antigens

In mice, it is well known that murine ERVs (MLV and IAP) often encode tumour antigens recognized by cytotoxic T cells.186,187 A corresponding mechanism was recently found in humans.188 Cytotoxic T lymphocytes specific for a short Env-derived peptide (MLAVISCAV) was detected in two patients with malignant melanoma. It is encoded from a 2578 bp retroviral RNA stemming from chromosome 16. The provirus belongs to the HERV-K(HML-6) group. Its name is HERV-K-MEL, or HERV-K(MEL,HML-6) according to the nomenclature of Andersson et al 11 The finding shows that even highly mutated ERVs can give rise to protein products with biological activity. HERV-K(MEL,HML-6) RNA was especially abundant in metastatic melanomas and in testis tissue.188 Moreover, the MLAVISCAV sequence is situated in the amino terminus of the HML-6 envelope protein (see Fig. 12), which is similar to the oncogenic envelope protein of JSRV, and to the disputed HML-2 superantigen of Conrad et al162 The tumor antigenicity, the similarity to known or alleged growth stimulatory betaretroviral envelope proteins, and the high expression of HERV-K(HML-6) located on chromosome 6 in a breast cancer,189 may mean that HERV-K(HML-6) encodes a surface oncoprotein, which is upregulated in a variety of tumours. It is too early to speculate on a functional role for HERV-K(HML-6) in human cancer. It does, however, merit further investigation. An important aspect is that HERV-K(HML-6) peptides could be used to elicit tumor immunity.

Herpesvirus—ERV Interaction: Does EBV Use a HERV for Stimulation of B Cell Growth?

The Marek disease herpesvirus of turkeys (MDV) can transduce avian leukosis virus (ALV).190 Such recombinant MDV is more lymphomagenic than MDV which does not contain ALV. This is an example of herpesvirus pathology enhanced by a retrovirus. Herpesviruses are highly prevalent in many species. In humans, human herpesvirus 7 (HHV7), Epstein-Barr Virus (EBV), human herpesvirus 6 (HHV6), Varicella-Zoster Virus (VZV) and Herpes Simplex type 1 (HSV1) are the most prevalent. They infect over 60% of the population and can then remain latent for a lifetime (for an overview, see Richman et al ref. 191). In this respect the herpesviruses are almost as "endogenous" as HERVs which often are present in 99-100% of the population. Thus, it is not unlikely that these viruses may utilize each other. The love and hate relationship between the human organism and a HERV then becomes a triangle drama. The MDV - ALV interaction may not be the only herpes-retrovirus interaction. It was recently found that the immediate early protein ICP0 of herpes simplex can transactivate the LTR of HERV-K(HML-2)192 (a similar finding was however reported much earlier193). In an intriguing series of experiments, Thorley-Lawson's group got evidence for a HERV-K(HML-2) env superantigen mediated stimulation of T cells after EBV infection.194 The growth stimulation was abrogated in the presence of anti-HERV-K(HML-2) antibodies. The suggested chain of effects is reminiscent of that of MMTV, which also activates a T cell to secrete B cell growth factors via a viral superantigen in order to stimulate growth of its host cell, the B cell. In this case, the benefactor allegedly is EBV. These findings need confirmation, but they emphasize the potential of interactions between highly prevalent selfish genes/retroviruses and ubiquitous exogenous viruses like the herpesviruses.

EBV is considered a major cause of lymphomas. The putative involvement of the HERV protein in EBV-related growth stimulation of B cells raises the possibility that immunization against the HERV protein, or prevention of its expression via transduction of anti-sense constructs, might inhibit EBV lymphomagenesis. This would be a logical consequence of the results of Sutkowski et al194 There are many reasons to clarify this issue (see below).

Autoimmune Disease

Chronic virus infections, including retroviral ones, may induce autoimmune phenomena.195 It is conceivable that a variable virus occasionally will present self-like epitopes, which may lead to a breach of tolerance. HERV encoded proteins basically should be perceived as self. Despite this, IgM anti-HERV antibodies occur in healthy persons (Lawoko et al,196 who used synthetic peptides), and in disease (IgG; Sauter et al,149 who used recombinant proteins). The occurrence of anti-HERV IgG during HIV infection may be due to presentation of variable epitopes more or less similar to HERV epitopes.196

The HERV-Diabetes Connection

An increased virus particle production in explanted pancreatic islets from juvenile diabetes, containing genomes of an hml2 variant here referred to as HERV-K(IDDM,HML-2), earlier called IDDMK1,2-22 or HERV-K18, was reported.162 This provirus is located on chromosome 1q21.2 - q22.197 A superantigen in the aminoterminal portion of the predicted Env protein of this virus was also reported. Several negative reports have accumulated since then.198,199 There was no difference in frequency of HERV-K(IDDM,HML-2) RNA in plasma between IDDM and controls. The superantigen effect could not be reproduced. The frequency of HERV-K(HML-2) antibodies in plasma was the same in patients and controls.200,201 Two recent publications did however succeed in demonstrating a superantigen effect.194,202 The same authors also connected the HERV-K(HML-2) superantigen with the B cell growth stimulatory effect of EBV (see above).

Thus, the possibility of a superantigen property in the aminoterminal portion of HERV-K(HML-2) Env remains open. Whether it corresponds to a conserved amino acid motif in the amino terminal portion of some human endogenous betaretroviral Env sequences189 (Fig. 12; see above) is uncertain. Clarification of this issue is important.

Presence of two other partial Class II sequences, HERV-K(HML-6)11,13,145,189,203 and HERV-K(HML-4), also referred to as HERV-K(T47D)83, among the histocompatility genes on chromosome 665 confers an increased risk of juvenile diabetes. The correlation may be caused by histocompatibility antigen alleles, MHC-associated HERVs, or a combination of them.

Systemic Lupus Erythematosus (SLE)

A HERV may have a physiological function within the complement system, which is also situated in the MHC region. Some alleles of complement factor 4 contain HERV-K(C4,HML-10). Absence of HERV-K(C4,HML-10) is related to systemic lupus erythematosus (SLE), a serious autoimmune disease.204 It is however not known if the HERV-K(C4, HML-10) gene is directly involved in the pathogenesis of this type of SLE. It could simply be a marker of other genetic events at the C4 locus.

Another aspect of SLE is DNA methylation. Certain drugs used in humans, i.e., prokainamide, are known to be inhibitors of DNA methylation. They can induce SLE.205 An increased RNA expression of HERV-E(4-1) was found in SLE patients.206 Treatment of PBMC with a demethylating agent gave a pronounced increase of HERV-E(4-1) expression in healthy controls, but no further increase in SLE patients.207 How this relates to autoimmunity is not known, but it does emphasize a possible involvement of demethylation of normally methylated sequences (which often are retrotransposons) in SLE. Examples which advocate methylation as a central mechanism for control of retrotransposons are i. a dramatic increase in retrotransposon activity, probably due to undermethylation, which was described in an hybrid of two wallaby species,208 and ii. undermethylation of retrotransposons in some human tumours.209

A third aspect is immune dysregulation. SLE patients have increased amounts of IgG antibodies reactive with certain HERV peptides.210,211 However, a similar increase was also found in HIV infected patients.196 In contrast, IgM antibodies reactive with the same peptides occurred in most healthy controls. IgG reactive with the same peptides did not occur in them. It was therefore suggested that HERVs may induce broadly reactive “natural” IgM against retroviruses. However, HIV infected persons frequently had IgG directed against the same set of peptides, suggesting an Ig chain switching event due to antigenic stimulation. Natural immunity in the form of IgM is an important protective factor against several microbes and it is conceivable that it can influence the course of retrovirus-induced disease. We currently believe that the increased levels of certain anti-HERV IgGs are symptoms of immune dysregulation rather than causes of SLE. The connection between HERVs and SLE has been reviewed,212 as well as between HERVs and autoimmune disease.195

Other Autoimmune Diseases

HERV RNA (ERV-9, HERV-K, HERV-L) expression in synovial fluid cells has been reported.213 The connection to rheumatoid arthritis (RA) seems tentative. The HLA-DQB1 locus has alleles associated with RA. They contain an HERV-K(HML-6) LTR.214

Placentation Defects

The evidence for a retroviral contribution to human physiology is relatively strong in some cases, more tentative in others. Theoretically, any of these functions can have its malfunction, i.e., disease. The case for a functional contribution is rather strong for placenta. Pleiotrophin,143 endothelin B receptor22 and syncytin121 are three important proteins which are highly expressed in placenta under the control of retroviral promoters. Moreover, many HERVs are highly expressed in placenta both as RNA144,215 and protein.216,217 Loss of retroviral mechanisms may therefore be serious for placental function. Indeed, several recent reports indicate that abnormal placentation and function (i.e., preeclampsia) are associated with abnormal expression of the HERV-W envelope protein, Syncytin.218

These data indicate a role for ERVs in placenta function. However, many questions remain. The placenta organ evolved gradually during the last 130 million years.219,220 The primate variant (a placenta with three tissue layers between fetal and maternal circulation, a hemochorial placenta) formed 40-50 million years ago. This structure is different from that of rodents who have a hemendothelial (1 layer-) placenta. Dogs and cats have an endotheliochorial (4 layer-) placenta. Ruminants have a syndesmochorial (5 layer-) placenta. Pig, horse and donkey have an epitheliochorial (6 layer-) placenta structure.221 All known HERVs implicated in the growth and differentiation of the human placenta (HERV-E.PTN, HERV-E(Endothelin B receptor) and HERV-W) integrated after the formation of the present type of placenta in human ancestors. HERV-E.PTN integrated 25 Mya i.e., long after this, and even after the split of Old and New World monkeys. The evolutionary and functional importance of HERV-E and HERV-W integrations should be studied by a comparison of placentas of Old and New World monkeys, because the latter ones do not have HERV-E and HERV-W. Thus it is likely that these relatively recent events only modulated preexisting mechanisms. Despite this, HERV-E.PTN LTR driven transcription is necessary for growth of trophoblast and choriocarcinoma cells in cell culture143 (Fig. 9). The HERV-E.PTN LTR also confers strict placenta specificity of expression (Fig. 14).

Figure 14. The HERV-E.

Figure 14

The HERV-E.PTN LTR confers strict placenta specificity of pleiotrophin (PTN) expression. HERV-E.PTN integrated into the human, but not the mouse, PTN gene. Homologous exons corresponding to the ORF (O1 to O4) or 5'-UTR (U2, U1) of the human (A) and the (more...)

Genetic Disease (Gene Loss) Due to Illegitimate Recombination between HERV Sequences

Illegitimate recombination occurs between adjacent and highly similar repetitive elements. Several recent reports indicate that HERV participation in this elimination process is not uncommon.222

The Sertoli-only syndrome with azoospermia due to loss of 792 kb which include the Azoospermia factor a (AZFa, also named DYS11) is caused by illegitimate recombination between HERV15yq1 and HERV15yq2, both situated at Yq11.223,224 This is a common cause of male infertility (Fig. 15).

Figure 15. Loss of the DYS11 (containing the azoospermia factor, the AZFa gene) region on chromosome Yq11 through illegitimate intrachromosomal recombination between two HERV-I, also known as HERV15, genes.

Figure 15

Loss of the DYS11 (containing the azoospermia factor, the AZFa gene) region on chromosome Yq11 through illegitimate intrachromosomal recombination between two HERV-I, also known as HERV15, genes. This leads to total loss of sperm production (azoospermia). (more...)

Other Diseases

It was recently reported that HERV-E env was transcribed in alveolar macrophages obtained by bronchoalveolar lavage from 3 cases of idiopathic pulmonary fibrosis and 3 cases of sarcoidosis, but not in PBL. Antibodies to HERV-E was also detected in the same fluid.225

What Can Be Done to Demonstrate a HERV-Disease Connection?

Most HERVs obviously are harmless because all human cells and all individuals have essentially the same set of HERVs. Because of their ubiquity it is especially difficult to establish a relationship between HERVs and disease. The correlations may be both positive and negative. Both heredity and environment can be influential. The example with the neurological disease in the mice at Lake Casitas shows how an ERV can be tied to a disease by detection of its genotypic and phenotypic properties. Potential genotypic markers of a HERV are new integrations and point mutations. Only a few of the former have been found.59 Integrational polymorphism of ERVs is common in mice226 and fowl.227 Point mutations (SNPs) in HERVs seem to be relatively common.70,71,228,229 An average HERV sequence gets 0.2% point mutations per million years.189 HERVs are often 10-40 million years of age. Thus, they often contain several per cent mutations of which some differ between individuals. On top of this, there may be a somatic HERV variation (see above). Phenotypic changes can be detected at the RNA or protein levels. There are several reports on a correlation between HERV expression and disease84-87,97,99,115,118,122,152,162,230 (see also in other portions of this article).

Proof of a HERV etiological involvement beyond statistical correlations may be hard to achieve. The Koch postulates or similar rules adapted to present-day techniques mainly pertain to exogenous agents.231 HERV gene knockouts other than naturally occurring polymorphisms are impossible in humans, but may be done in cell culture. The strategy therefore often must be one of guilt by association. The tools will be sequencing of genomic DNA and cDNA, RNA quantification, promoter/enhancer studies and protein detection. There is precedence in animals for disease caused by XRV infection just after birth, or early activation of ERVs, followed by a chronic viremia which later develops into disease. Such temporally separated events should therefore be looked for.

Conclusions

Because endogenous retroviruses are a type of transposon, “jumping gene”, one expects them to integrate into new loci in the human genome. Such “jumps” have hitherto not been observed in vivo. Individual-specific integrations observable at the germ line level indicate that more frequent transpositions also occur at the somatic level. Most somatic integrations will not be seen in the germ line. The selection pressure at the somatic level is more varied. The likelihood that transposition at this level will be compatible with cellular survival therefore is greater. The finding of Jack Lenz'group59 has increased the likelihood that humans have intact and active HERVs which theoretically are infectious and therefore could have a similar pathogenic status as MMTV in mice.

Humans, like all other eukaryotes, have a number of more or less functional endogenous retroviruses or retrovirus-like transposons. The plenitude of HERVs (Fig. 2) shows that there have been many more exogenous retroviruses in the forefathers of humans than the four human exogenous retroviruses known today (HTLV-1 and -2, HIV-1 and -2). Many of them may have died out as exogenous retroviruses, but some may survive as exogenous, infectious, viruses in an animal more or less related to humans, or even in humans themselves.

The new information leaves many questions: Are there really infectious HERV particles? Which are the physiological roles played by HERVs? In this review we have analysed the pathogenic potential of HERVs from an evolutionary perspective. Although the great majority of HERVs probably will prove not be pathogenic,140 there is now enough information to justify a search for correlation to human disease. There are leads for further research on seminoma, MS, schizophrenia, placental defects, gene loss and SLE.

Acknowledgements

We thank Tove Airola, Dixie Mager and Robert Yolken for critical reading of the manuscript and valuable suggestions.

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