GENERAL BIOLOGY OF ENDOGENOUS RETROVIRUSES
Avian leukemia virus and Rous sarcoma virus were the first retroviruses discovered, and diverse groups of enveloped RNA viruses belong to the retrovirus family (1, 2). The retroviral virion RNAs are positive and single-stranded and range from 7 to 12 kb in size (3-5). Subsequent to infection, the retroviral virion RNA is reverse transcribed into a double-stranded DNA copy using the viral reverse transcriptase and is followed by a random integration into numerous host genomic loci as a provirus.
Retroviruses usually infect somatic cells; however, they infect germline cells on occasion, leading to a permanent integration of proviral forms into the germline genome (6). These germline-integrated retroviruses, called endogenous retroviruses (ERVs), are inherited to the offspring in a Mendelian fashion. In contrast, the exogenous retroviruses, which are acquired from the hosts' surroundings, are predominantly transmitted horizontally. Primarily due to the random nature of the proviral integration process, it is likely that each individual has a unique profile of ERVs derived from both maternal and paternal genomes.
Full-length ERVs retaining essential coding potentials for virion assembly are capable of continuing their life cycle, resulting in further downstream genomic integrations. However, the accumulation of mutations (missense, deletion, insertion, and recombination) in the viral genome renders the affected ERVs defective in regard to the expression of retroviral polypeptides; thus, they are often called "junk DNAs" (7). In particular, recombination may be one of the key contributing factors responsible for the abundance of defective ERVs in the genome (6). It is likely that the constant and dynamic interactions among the host, its genomic resident ERVs, and a range of environmental stressors, such as injury, infection, and hormones, play central roles in shaping the host's ERV profile, primarily in somatic cells.
All retroviruses, including ERVs, have two identical long terminal repeats (LTRs) flanking the coding sequences. Long terminal repeats consist of U3 (3′ unique region), R (repeat), and U5 (5′ unique region) (Fig. 1). The U3 sequence located on the 5′-LTR serves as a viral promoter. The expression of ERVs is primarily controlled by host cellular transcription machinery in association with the specific transcription regulatory elements on their U3 promoters (8). Nuclear and cytoplasmic compartments of individual cells maintain a unique pool of transcription factors and other components of the transcription machinery, such as the spliceosome. A wide range of stress signals (e.g., injury, infection, oxidative stress, psychological stress) from the surroundings at cell, tissue/organ, and/or system levels may differentially alter their transcription environment either for the short or long term, depending on the nature of the stressors and the host's responses. Furthermore, the epigenetic status of individual ERVs and chromatin high-order structure near their integration loci may play a crucial role in controlling ERV expression (9).
The fact that ERVs constitute a substantial fraction of the genome may suggest their substantial roles in an array of host pathophysiology. Certain ERV transcription regulatory elements are capable of controlling the expression of host genes neighboring and distant through various mechanisms, such as intergenic splicing, polyadenylation, enhancer activity, and suppression of translation (10-12). Endogenous retroviruses also contribute to chromosomal rearrangement by insertional mutagenesis and homologous recombination, mainly between LTR sequences.
MAMMALIAN GENOMES, TRANSPOSABLE ELEMENTS, AND ERVs
Recent availability of the genome database for a number of mammalian species has facilitated further research into transposable elements, also known as mobile genetic elements and often as "junk DNA" (13, 14). A substantial fraction of various mammalian genomes is composed of diverse classes of transposable elements (15). Transposable elements, which make up ~45% of the human genome, are primarily composed of DNA transposons (~2.8%) and retroelements (~42.2%) (7, 16, 17) (Fig. 2). Retroelements (e.g., ERVs, Alu elements) require RNA intermediates, which are then reverse transcribed into a DNA form, before transposition into various genomic loci, whereas DNA transposons can transpose without RNA intermediates. There are two main groups in human retroelements: LTR retroelements (~8.3%) and non-LTR retroelements (~33.9%). Long terminal repeat retroelements are composed of ERVs and ERV-derived elements, such as solo LTRs, and short interspersed elements (SINE)-R (7, 16). Thus far, ERVs have been identified in all vertebrates examined (18-20). Non-LTR retroelements are primarily represented by SINEs (~13.1%) and long-terminal interspersed elements (~20.1%) (21). Alternatively, Boeke and Stoye (6) classified retroelements into eight subfamilies: ERV, LTR retrotransposon, poly(A) retrotransposon, pararetrovirus, retroplasmid, retrointron, retrotranscript, and retron. Interestingly, retroelements harboring coding potentials for the retroviral envelope domain have also been identified in drosophila and plants (22, 23).
Human LTR retroelements have been divided into six subfamilies by Medstrand et al. (21): class I ERV, class II ERV, class III ERV, MER4 (class I-related ERVs), MLT (mammalian LTR transposons), and MST (named for a shared MstII site) (16, 21). In addition, the human ERV (HERV) family has been classified into seven subfamilies based on their genomic sequences, whereas 26 HERV subfamilies were defined by another group of studies (24-26). The class I HERVs are similar to the type C (γ) retroviruses (e.g., murine leukemia virus [MuLV]), whereas classes II and III HERVs are related to type B (β) retroviruses (e.g., mouse mammary tumor virus [MMTV]) and spumaretroviruses (e.g., chimpanzee foamy virus), respectively (27, 28). The genomic organizations of representative HERV, MuLV-type murine ERV (MuERV), MMTV-type MuERV, and porcine ERV (PERV) are illustrated in Figure 1. The HERV nomenclature, which is based on the tRNA primer binding site (PBS), is frequently cited; however, it seems there is a limitation in using this system because some PBSs are shared by a number of HERVs that are distantly related (29). Recent advances in genomics research may contribute to the establishment of a comprehensive classification system for HERVs as well as other LTR retroelements.
The genomes of most inbred laboratory strains of mice are known to harbor at least eight different subfamilies of LTR retroelements, including MuERVs whose genomic organizations are similar to MMTV and MuLV (30-32). Among these subfamilies, only MuERVs (MuLV-like and MMTV-like) have closely related exogenous counterparts, type C (MuLV) and type B (MMTV) retroviruses (33, 34). The presence of the exogenous counterparts suggests that these MuERVs have transposition potential. Only a limited number of MuERVs are presumed to be capable of assembling virion particles followed by productive infection and reintegration. The others may encode only defective virion RNAs, some of which require a full-length helper virus for their virion assembly. In addition, these defective MuERVs may recombine with replication-competent proviral loci, resulting in recombinant MuERVs with unique biological properties including infectivity and tropism traits (35-37).
INVOLVEMENT OF ERVs IN PATHOPHYSIOLOGIC PROCESSES INCLUDING INJURY AND INFECTION
Recent studies demonstrate that some ERVs are biologically active and that they may participate in a range of pathophysiologic processes in humans and animals. The following is a summary of recent data related to the involvement of ERVs in various pathophysiologic processes, including injury and infection, of humans, mice, sheep, and pigs (Table 1).
Several studies provide evidence that HERVs are involved in various disease processes, including schizophrenia, systemic lupus erythematosus (SLE), breast cancer, multiple sclerosis (MS), and type 1 diabetes mellitus (38-40). The expression of the HERV-W (a member of class I HERV) envelope glycoprotein, called syncytin-1, is induced in the glial cells of the brain tissues from MS patients (41-43). The proinflammatory properties of syncytin-1 and its involvement in the onset of MS demonstrated a unique role of HERVs in inflammatory diseases. Another member of class I HERV, called HERV-E (clone 4.1), has been implicated as a causative agent of SLE (44). The envelope proteins of the HERV-FRD family (a member of class I) contribute to the formation of pseudotype infectious virions (45). In addition, the fusogenic properties of two envelope proteins encoded from HERV-W (syncytin-1) and HERV-FRD (syncytin-2) are demonstrated by their expression in the syncytiotrophoblasts, which are directly involved in placental morphogenesis (46, 47).
Retroviral particles have been detected in various human tissues, including malignant tumors, and cell lines (48-52). In particular, the T47-D human breast cancer cell line produces retrovirus-like particles, which harbor types B and C virion RNAs, presumably derived from HERVs. In addition, several studies have reported that the expression of HERV-R is tissue-specific and developmentally regulated, suggesting its potential role in differentiation (53, 54). It has been suggested that ERV-9 LTR enhancers may control the expression of a group of cis-linked genes essential for embryogenesis in humans (55, 56). Furthermore, an LTR transposon derived from the ERV-9 family has been identified within the locus control region of the β-globin genes, and it appears that its enhancer activity may contribute to the regulation of β-globin expression (57).
The human teratocarcinoma-derived virus (HTDV), also known as a member of the HERV-K family, a class II HERV, retains its coding potential for essential retroviral polypeptides for virion assembly (58). Class II HERVs are also called human MMTV-like (HML) ERVs. The expression of HTDVs is induced in testicular tumors, and its promoter is highly specific for these tumor cells (59). The IDDMK1,222 HERV, another member of the HERV-K family, is reported to be expressed in leukocytes of patients with type 1 diabetes (38). This HERV encodes a T-cell receptor (TCR) Vβ7-specific superantigen (SAg). Type 1 diabetes is an autoimmune disease mediated by T cells, and it is probable that the IDDMK1,222 HERV-encoded SAg is responsible for the Vβ7+ T-cell enrichment in the pancreatic islet of the patients.
Among the eight subfamilies of murine retroviral elements, MuLV-type and MMTV-type MuERVs are known to have exogenous counterparts. Although a comprehensive genomic MuERV map has not yet been established, it appears that the genomic copy number of MuLV-type MuERVs is substantially higher than the MMTV-type in all laboratory strains examined so far (6). Murine leukemia virus-type MuERVs can be divided into four groups based on tropism traits: ecotropic, xenotropic, polytropic, and modified polytropic (60).
The MuLV-AKV virus, which was identified in the AKR mouse genome, is a typical ecotropic (capable of infecting mouse cells) MuERV, and it has been implicated in the onset of spontaneous thymic leukemias in AKR mice (61, 62). Interestingly, the ecotropic MuLV-AKV undergoes a recombination event with a nonecotropic MuERV, generating a recombinant virus, called MCF (mink cell focus-inducing) MuLV (63). The presence of MuLV-MCF proviruses in the genomes of leukemic thymocytes suggests that the recombinant MuLVs are the primary causative agent of the thymic leukemias in AKR mice (64). These findings suggest that recombination events between MuLV-type MuERVs with different tropism traits may be an important step for the onset of specific disease states.
Furthermore, recent studies from our laboratory demonstrate that the expression of a number of xenotropic and polytropic MuERVs (MuLV-type) is differentially regulated in various tissues (e.g., liver, lung, spleen, bone marrow, thymus, blood) of mice after burn injury and cecal ligation and puncture (CLP)-induced sepsis (Ref. 8; unpublished data). Interestingly, the genomic organization of some of these MuERVs is similar to the murine acquired immune deficiency syndrome (MAIDS)-inducing virus (36, 65, 66). The LP-BM5 MuLV mixture, which was isolated from radiation-induced leukemia in C57BL mice, has three types of MuLVs (67, 68). Two types of replication-competent viruses present in the LP-BM5 mixture, including MuLV-MCF, serve as helper viruses. The p12 protein within the gag polypeptide of the defective 4.9-kb MAIDS virus, which is the third component of this mixture, appears to be responsible for the development of the immune disorder.
Data from our laboratory reveal that a substantial number of full-length MuERVs (MuLV-type) with intact coding potentials for all three essential polypeptides are likely to be involved in postburn injury response (8). Interestingly, we observed that treatment of control no-burn animals with anesthetic agents (isoflurane and ketamine/xylazine) alone followed by resuscitation with saline and narcotics affects the expression of certain MuERVs (8). Murine leukemia viruses have been regarded as simple retroviruses because their coding potentials are reported to be limited only to three essential polypeptides in conjunction with their splicing potentials. It turns out that injury (burn)- and infection (CLP-induced sepsis)-elicited stress signals are associated with the expression of a range of MuERV splicing variants in a tissue-specific and time-dependent manner (65, 66, 69; unpublished data).
Infectious MMTVs, initially identified as the milk agent virus, are found in high concentrations in mammary alveoli and mammary adenocarcinomas (70). The genomic distribution of the endogenous MMTV loci is relatively well characterized, and a standardized nomenclature system has been established (71). The genome of each inbred mouse strain consists of a limited number of endogenous MMTV loci, and individual loci have their own designations, such as Mtv-1 and Mtv-2. For instance, C57BL/6 and C57BL/10 genomes have three loci (Mtv-8, Mtv-9, and Mtv-17).
Both Mtv-1 and Mtv-2, which were the first two endogenous MMTVs identified, produce infectious virions and are associated with the genetic transmission of mammary adenocarcinomas (72). It has been reported that the reintegration of proviruses of the Mtv-2 locus-derived infectious MMTVs into specific loci, such as int-1 and int-2, is responsible for mammary tumorigenesis (73, 74). The findings that certain endogenous ERVs, such as Mtv-2 in mice, are capable of producing infectious virions suggest that ERVs' constant interactions with stress signals, such as injury and infection, from the surroundings may be followed by ERV activation and subsequent random reintegration into the host genome. It will be important to investigate the biological significance of the accumulation of ERVs' genomic reintegration events, if any, in a range of acute as well as chronic pathogenic processes in humans and animals.
A variety of microorganisms, such as MMTV, rabies virus, staphylococcus, streptococcus, and mycobacterium, encode SAgs (75). A significant fraction (5%-40%) of the T-cell repertoire can interact with a single SAg, whereas conventional peptide antigens interact with only 1 in 104 to 1 in 106 T cells (Fig. 3). Minor lymphocyte stimulatory (Mls) antigens, which were identified more than three decades ago, are capable of eliciting a strong T-cell response between mouse strains sharing the same major histocompatibility complex (76). It turns out that Mls antigens are SAgs encoded from an open reading frame located in the 3′-LTR region of all endogenous MMTVs identified so far (77). In contrast to the recognition of conventional peptide antigens through the antigen binding grooves of the TCR α:β chains specific for each antigen, SAgs bound to major histocompatibility complex II interact primarily with the variable region of the TCR β chain (Vβ) (Fig. 3) (78). A hypervariable region near the C-terminus of SAg proteins is directly responsible for the TCR Vβ specificity of different SAg isoforms (79).
A recent report demonstrates that burn injury-elicited stress signals are associated with the proliferative responses of several subpopulations of Vβ T cells (Vβ4+, Vβ6+, Vβ11+, and Vβ14+) (80). Our preliminary data reveal that there is an increase in expression of endogenous MMTV mRNAs, which span the SAg coding sequence, in the lymphoid tissues (spleen and thymus) of Institute of Cancer Research (ICR) mice in response to CLP-induced sepsis development (unpublished data). It has been well documented that stress signals from injury and infection can activate the hypothalamus-pituitary-adrenal (HPA) axis, resulting in increased systemic glucocorticoid levels. Certain MMTVs and MuLVs are known to have a distinct transcription regulatory element, called the glucocorticoid response element, which binds the activated form of the glucocorticoid receptor complex (Fig. 4). It is possible that the increase in MMTV expression in the lymphoid tissues of CLP mice might be associated with the sepsis-induced increase in systemic glucocorticoid levels. In turn, the endogenous MMTV SAgs may play a role in the development of immune dysregulation, especially the T-cell response, during pathogenic processes associated with injury and infection.
Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus are oncogenic type D retroviruses, and they cause infectious ovine pulmonary carcinoma and nasal neoplasm, respectively (81, 82). There are approximately 15 to 20 copies of type D-related ERVs in the sheep and goat genomes, which are highly related to the exogenous JSRV and enzootic nasal tumor virus, and as a result, they are called endogenous JSRVs (enJSRVs). The presence of exogenous and infectious counterparts suggests that enJSRVs were integrated into the sheep genome relatively recently. In situ hybridization experiments reveal that enJSRVs are highly expressed in the luminal and glandular epithelia of the uterus (83). An in vivo experiment using an antisense oligonucleotide protocol demonstrates that the enJSRV envelope protein plays a crucial role in conceptus development and establishment of pregnancy (47). Furthermore, recent studies show that fusogenic syncytins (envelope proteins) of certain ERVs of humans, mice, and nonhuman primates are highly expressed in the syncytiotrophoblast layer at the maternal-fetal interface (46, 84-86). These findings suggest that ERVs of various mammalian species play an important physiological role in placenta morphogenesis and maintenance of pregnancy.
Porcine ERVs have been scrutinized extensively because of the biohazardous potential associated with the xenotransplantation of genetically engineered pig organs into human patients (87). Porcine ERVs are infectious type C retroviruses that are divided into three classes (PERV-A, PERV-B, and PERV-C) based on their tropism traits (88). It is estimated that there are approximately 50 PERV loci in the genomes of different porcine breeds (89). The primary concerns related to xenotransplantation with pig organs are PERVs' potential for infection into the cells of the xenograft recipient and subsequent generation of HERV-PERV recombinants with unknown pathogenicity. Patience et al. (87) demonstrated that a PERV produced from a pig kidney cell line (PK15) is able to infect and propagate in various human cell lines. It is likely that PERVs may not retain substantial pathogenicity within their natural genomic organization and host; however, potential rearrangement events between PERV and HERV genomes in an immunosuppressed setting are likely to be one of the most serious concerns associated with xenotransplantation.
EPIGENETICS OF ERVs AND RESPONSE TO STRESS SIGNALS
In addition to the DNA sequence itself, the function of the genome is further defined by the profile of diverse epigenetic modifications of DNA and histones, the key proteins responsible for the nucleosome unit formation and chromatin high-order structure (90). The expression of a wide range of genes is tightly controlled during the development of germline cells as well as in somatic cells via epigenetic modifications. Two primary epigenetic events include DNA methylation and histone acetylation (91, 92). The dynamics of changes in DNA methylation and histone acetylation (plus other modifications) are determined by intrinsic signals as well as stress signals derived from the surroundings at different levels (cell, tissue/organ, and system).
It is likely that changes in DNA methylation status and chromatin high-order structure, primarily determined by histone modifications, are directly linked to the regulation of ERV expression in conjunction with a given transcription environment, such as the pool of transcription factors and the ERVs' own transcription potential. We can speculate that genomic ERV profiles of different cells and tissues within one individual may vary because of differential ERV activation and random reintegration into the genome associated with the unique transcription environment and the epigenetic status in each cell and tissue. The expression of the majority of retroelements is repressed by hypermethylation of their genomic loci in unstimulated somatic cells to maintain genome stability (associated with retrotransposition) and to minimize aberrant expression of flanking host genes (13, 93).
Recent reports suggest that methylation status of certain HERVs is associated with carcinogenesis and autoimmune diseases (94, 95). It is probable that some stress signals (e.g., injury, infection, oxidative stress, psychological stress) may establish a hypomethylation status of certain ERV loci in conjunction with histone acetylation in the region, leading to their activation. In turn, activated ERVs may contribute to a range of pathophysiologic changes in affected cells and/or tissues, such as immune disorders, by increased retroviral activities and aberrant host gene expression. Further studies are needed to present a direct link between epigenetic status of retroelements and etiopathology of systemic response to injury and infection.
POTENTIAL ROLES OF ERVs AND THEIR GENE PRODUCTS IN SYSTEMIC RESPONSE TO INJURY AND INFECTION
Endogenous retroviruses represent substantial proportions of their respective host genomes, and it seems that they are involved in a number of pathogenic processes. In particular, ERVs may play crucial roles in a cascade of cellular and molecular events underlying the systemic pathologic alterations after injury and infection. They may exert biological effects via the regulation of their own as well as neighboring host genes at their integration sites, and it is not clear whether their participation in these processes is harmful or beneficial to the host. There are at least three potential mechanisms of how ERVs may participate in the systemic response to injury and infection (Fig. 5). First, certain ERVs may simply exist in the genome as genetic components like any other host genes, and their primary roles reside in the ability to encode retroviral proteins, such as gp70 envelope, SAg, p12, and p30 capsid, rather than to produce infectious virions for replication. In particular, gp70 envelope glycoprotein may be differentially expressed on the cell membrane in response to stress signals from injury and infection. In turn, the activated envelope glycoprotein may serve as a receptor to transmit signals stemming from the altered extracellular environment due to injury and infection. Second, a limited number of ERVs, which have intact coding potentials for all retroviral polypeptides required for the assembly of pathogenic and/or nonpathogenic virions, are activated in response to stress signals followed by reintegration into the genome and replication. Another group of ERVs retaining only defective viral genomes may be activated following stress signals; however, they may become pathogenic by recombination with replication-competent viruses or in the presence of full-length helper viruses. In fact, the genomic organization of the defective MuERVs induced in distant organs after burn and CLP-induced sepsis was very similar to the MAIDS-inducing virus, whose immune suppressive activity depends on the presence of full-length helper virus (65, 66). Third, changes in transcriptional activities of certain ERV loci in response to stress signals from injury and infection may affect the expression of neighboring host genes by enhancer/repressor activity, intergenic variant splicing, and alternative polyadenylation leading to pathophysiologic alterations in affected cells, tissues/organs, and/or systems. It is probable that these different ERV pathways may be activated simultaneously at multiple genomic locations during the systemic response to injury and infection. Alternatively, the diversity of ERVs reflected in the polymorphic U3 promoter and envelope sequences and differential epigenetic statuses allows for the ERV pathways to be selectively utilized depending on the nature and intensity of stress signals and differential stress responses.
CONCLUDING REMARKS: CLINICAL IMPLICATIONS
Critical illness associated with a major burn and sepsis includes immune disorders in conjunction with dysfunction of various distant organs. An array of molecules (e.g., lipopolysaccharide, TNF-α) and cell types have been linked to the development of burn- and sepsis-associated complications. However, it is still not clearly understood how the complex network of pathogenic events is coordinated in response to the stress signals stemming from burn and sepsis. Stress signal-elicited activation of certain ERV loci in conjunction with the regulation of their flanking host genes may be networked into a cascade of signaling events responsible for the pathogenesis of burn and sepsis. It is probable that the heterogenic nature of HERV profiles among the human population may, at least in part, account for the substantial variability in the clinical manifestations in response to burn and sepsis (Fig. 6).
Understanding the effects and underlying mechanisms of the activation of certain ERVs after burn and sepsis will broaden insights into the pathogenesis of systemic immune disorder and organ failure in these patients. It may ultimately lead to the development of a novel therapeutic protocol for burn and sepsis patients (Fig. 7). The new treatment regimens may include antiretroviral treatment using the currently available inhibitors for retroviral protease and/or reverse transcriptase as well as siRNAs and antibodies designed specifically for individual ERV gene products.
The authors thank Sophia Chiu, Karen Hsu, Debbie Lim, and Dr. Deug-Nam Kwon for assistance in creating the figures.
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