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Journal of Virology, December 2003, p. 12385-12391, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12385-12391.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

MINIREVIEW

Comparative Pathogenesis of Epsilonretroviruses

Donald Holzschu,1* Lorie A. Lapierre,1 and Michael D. Lairmore2,3,4

Department of Biological Sciences, Ohio University, Athens, Ohio 45701,1 Center for Retrovirus Research and Department of Veterinary Biosciences,2 Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Solove Research Center,3 Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 432104


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INTRODUCTION
 
Experimental models using mammalian and avian oncogenic retroviruses have led to key advances in the understanding of cell proliferation and oncogenesis and basic principles in cell biology. Since the discovery in 1911 of Rous sarcoma virus (65, 66), more than 30 oncogenes have been identified in acutely transforming simple retroviruses (reviewed in references 17 and 62). Retrovirally transduced oncogenes include transcription factors, growth-stimulating factors, receptor molecules, protein tyrosine kinases, protein serine/threonine kinases, and membrane-associated G proteins (62). Each of these retrovirus-encoded oncogenes has a highly conserved cellular counterpart, and many of their human homologs have been implicated in cancers. In contrast to the simple retroviruses, oncogenic complex retroviruses, e.g., human T-cell lymphotropic virus type 1, do not contain typical oncogenes but contain unique regulatory and accessory genes that are believed to promote cancer through their ability to alter cellular gene regulation (1). These studies have contributed greatly to our understanding of eucaryotic cell cycle regulation and cell proliferation, but these processes are still far from understood. Therefore, it is important to continue to develop new research venues for the study of cell proliferation, including new systems to study retrovirus-induced oncogenesis. Piscine and other retroviruses of lower vertebrates represent an untapped resource of model systems to investigate mechanisms of oncogenesis. At least 13 proliferative lesions of fish are tentatively attributed to retroviruses based on the observation of retrovirus-like particles and, in some cases, reverse transcriptase activity in lesions. Interestingly, seven of these lesions are seasonal; i.e., they develop and regress annually, thereby providing unique experimental models for tumor development and naturally occurring tumor death (Table 1) (25). This review focuses on the skin lesions of walleyes (Stizostedion vitreum), i.e., walleye dermal sarcoma (WDS) and walleye epidermal hyperplasia (WEH) and on their associated epsilonretroviruses, WDS virus (WDSV) and WEH viruses 1 and 2 (WEHV1 and WEHV2).


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  		TABLE 1. Seasonal hyperproliferative lesions of fish putatively associated with retroviral infections


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WDS AND EPIDERMAL HYPERPLASIA
 
WDS and WEH were first reported on fish from Oneida Lake in New York by Walker (76), who later observed type C retrovirus-like particles in lesions (75, 76). Subsequently, WDS and WEH have been reported on walleyes throughout North America (9, 79). Both WDS and WEH are common in areas of endemicity; nearly 30% of the adult walleyes collected during the spring spawning run from Oneida Lake present WDS in some years, while approximately 10% present WEH. Lesions are present in late fall through early spring, when they regress (Fig. 1) (2, 11, 25, 60). WDS of feral walleyes is a multifocal, benign skin lesion that can first be seen in the fall as firm, vascularized tumors (Fig. 1). In contrast, WEH is a multifocal hyperproliferative skin disease that can first be seen in the fall as sharply delimited plaques of thickened epidermis (Fig. 1) (76, 80). Regressing WDS lesions are seen in the spring during the walleye spawning run and are soft and pale and are being shed. There is no obvious shedding of WEH during the spring spawning run, and it is thought to regress later in the spring. There are no documented cases of WDS or WEH leading to the death of a feral walleye, suggesting that regression is complete.



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  		FIG. 1. Retrovirally induced skin lesions of walleyes. (A) Raised tumors (arrow) typical of WDS on the flank of walleyes caught in the fall of the year. (B) Mucoid lesion (arrow) typical of WEH on the upper surface of a walleye caught in springtime. (C) The seasonal cycle of these diseases. The lesions shown in panels A and B will completely regress, leaving no scars.

The molecular and cellular events leading to the seasonal induction and regression of WDS are not completely understood but are likely to include complex interactions of viral and host factors, e.g., hormonally regulated changes in viral gene expression and variations in the immune response of fish at different water temperatures (2, 11, 31, 42, 61). A number of observations support this view of pathogenesis, including (i) the presence of abundant retrovirus type C particles in regressing tumors but not in developing tumors (14), (ii) observations that the gene expression patterns of the walleye retroviruses change both quantitatively and qualitatively during the course of the disease, with low levels of spliced RNA transcripts produced in developing tumors and high levels of spliced and unspliced viral transcripts produced in regressing tumors (42, 61), and (iii) the experimental transmission of disease to walleye and sauger (a closely related species that interbreeds with walleye [Stizostedion canadense]) fingerlings by using cell extracts from regressing tumors but not from developing tumors (8, 10, 12, 14, 19, 32, 48). WDS has been transmitted to walleye fingerlings by using cell-free tumor filtrates as inocula and by waterborne exposure (8, 12-14, 48). Generally, experimental transmission studies done with walleye fingerlings have produced WDS in 10 to 14 weeks that are typical of those seen in the fall on feral fish. Importantly, they have also resulted in the generation of invasive tumors (19). Invasive dermal sarcomas have also been observed on experimental sauger fingerlings (32). These experiments demonstrate that WDSV has the potential to induce lethal tumors and suggest that tumor regression arose from an adaptive process that benefits both the virus (regressing tumors release copious numbers of virions) and host. Tumors of other organs have not been observed in experimental fingerlings or feral adults (60). WEH has also been experimentally transmitted to walleye fingerlings by intramuscular injection of cell-free filtrates from hyperplastic lesions (7). While WDSV and the WEHVs are considered to be the etiological agents of WDS and WEH, definitive proof awaits transmission studies with infectious molecular clones.

Presently, there is no direct evidence demonstrating that the epsilonretroviruses reinfect feral walleyes and cause tumors or hyperplasias in subsequent years. However, a statistical analysis of fish collected over a number of years and scored for age and presence of tumors suggests that walleyes do not develop WDS in successive years (27). Additionally, it has been experimentally demonstrated that walleye fingerlings with WDS are more resistant to new tumor production than are fingerlings with no previous challenge (26). These data suggest that walleye fingerlings may be somewhat resistant to sequential infection, but it is not clear that this phenomenon relates to tumor development or regression on feral adult walleyes. Experimental evidence does not support a major role for the immune system in the regression of WDS or WEH. Coincident with WDS and WEH regression, the fish immune system is at its nadir in the spring when the water is at its coldest (2). Lymphocytic infiltration was described in regressing WDS lesions, but the advanced necrotic state of WDS lesions examined suggests that regression begins much earlier and that infiltration may be in response to secondary infection of regressing lesions by bacteria and fungi (26). Additionally, there is little to no inflammatory response associated with developing or regressing WDS (26).


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MOLECULAR CHARACTERIZATION OF WDSV AND WEHV1 AND -2
 
WDSV, WEHV1, and WEHV2 are the only retroviruses associated with seasonal proliferative skin lesions that have been molecularly cloned and sequenced (31, 42, 43, 47, 50). The genomic structures of WDSV, WEHV1, and WEHV2 are unique among the retroviruses (Fig. 2). They are the only retroviruses predicted to use a histidyl-tRNA for priming first-strand DNA synthesis, and they carry genes that encode a protein of approximately 14 kDa (orf-C) upstream of gag (31, 42). The predicted Orf-C proteins have no obvious similarity to other proteins, but the WDSV Orf-C protein has recently been shown to induce apoptosis in a heterologous cell culture system and may contribute to lesion regression (56). In addition, distal to env are two nonoverlapping open frames, orf-A and orf-B. orf-B is related to orf-A, suggesting that these genes arose by a gene duplication (42). Importantly, orf-A encodes a retroviral cyclin (rv-cyclin) that is distantly related to cellular D-type and C-type cyclins (41, 68). Some regions of these proteins also resemble cyclin A (82).



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  		FIG. 2. The genomic structure and mRNA transcripts of WDSV. The WEHVs have the same genomic structure. * represents open reading frames confirmed by protein sequencing. ** represents proteins partially purified from WDSV virions of enzymatic analysis; see text. The parentheses seen in the spliced mRNA species show the region over which multiple splice donors and acceptors have been identified (61).

While many different oncoproteins have been identified in avian and murine retroviruses, only the epsilonretroviruses harbor cyclin homologs (rv-cyclins), thereby providing a new paradigm of retrovirus-induced cellular proliferation (41). The rv-cyclins share only 20 to 25% amino acid identity with cellular D- and C-type cyclins, and they do not hybridize with walleye DNA (41, 68). By comparison, the cyclin D homolog of the Kaposi's sarcoma-associated herpesvirus (KSHV) has about 28% amino acid identity with human cyclin D1. The most highly conserved regions of cellular and rv-cyclins form the protein surfaces that interact with cellular cyclin-dependent kinases (Cdks). Each of the rv-cyclins has invariant lysine and glutamate residues in predicted {alpha}-helices C and E that are necessary for Cdk interaction and activation (38). The amino acid sequences of the WEHV cyclins are 37% identical within the cyclin box and 21 to 28% identical with the WDSV cyclin.


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VIRAL GENE EXPRESSION IN DEVELOPING AND REGRESSING LESIONS
 
Transcriptional mapping by reverse transcriptase PCR (RT-PCR) and Northern blot analyses of developing and regressing WDS and WEH have demonstrated temporal gene expression profiles and complex splicing patterns analogous to those seen in other complex retroviruses (Fig. 2) (42, 61). Northern blots showed that only very low levels of subgenomic viral transcripts, predominantly the full-length rv-cyclin transcripts, are present in developing lesions, implicating these proteins in the development of WDS and WEH. Additionally, orf-B mRNAs have been detected by Northern blotting in developing WDS but not in developing WEH (42, 61). In contrast, abundant levels of genomic, singly spliced env and orf-B and singly and doubly spliced orf-A transcripts are present in regressing WDS. In contrast, only singly spliced orf-A and orf-B transcripts have been identified by RT-PCR in regressing WEH. The molecular mechanisms responsible for the differences in the levels of gene expression and splicing patterns observed in developing and regressing lesions are not understood, but it has been shown experimentally that the WDSV cyclin represses viral transcription; see below (68, 82). The differences seen in viral gene expression in developing and regressing WDS and WEH are consistent with the finding that experimental transmission of WDS can be achieved only with cell-free inocula derived from regressing lesions (14).

Recently, it was suggested that only amino-truncated forms of the WDSV cyclin protein are produced in regressing tumors (61, 67). The data in these reports show, in agreement with earlier observations (41, 42, 61), that an mRNA encoding the full-length WDSV cyclin protein is the predominant orf-A transcript in developing tumors. In contrast with earlier reports, the full-length orf-A mRNA was not detected in regressing tumors when a probe homologous to the region of the mRNA encoding the amino terminus of the WDSV cyclin was used; see below (67). Alternatively spliced mRNAs encoding amino-truncated forms of the WEHV1 or WEHV2 rv-cyclins have not been detected in regressing lesions (42) and therefore do not appear to be used by the WEHVs during tumor development and regression. The copious amounts of viral RNAs present in regressing WDS and WEH could be toxic, thereby contributing to lesion regression.


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WDSV CYCLIN PROMOTES CELL PROLIFERATION
 
Experimental evidence has demonstrated the ability of the WDSV cyclin to induce cell proliferation. The WDSV cyclin supported growth of a yeast (Saccharomyces cerevisiae) strain, BY613, conditionally deficient for the synthesis of G1-to-S cyclins that are necessary for cell cycle progression (41). The WEHV rv-cyclins did not support yeast growth, and the reasons for this are not known. However, it is documented that the human PRAD1 gene (cyclin D1) also does not work well in this system. The important result was that the WDSV cyclin did support growth, suggesting that the rv-cyclins are capable of affecting cell cycle progression and tumor development and growth. Additionally, the WDSV cyclin has been shown to induce cell proliferation in transgenic mice (40).

Numerous transgenic mouse models have been used to analyze the oncogenic properties of cellular cyclins (A, D1, D2, D3, and E) and viral cyclins (gammaherpesviruses and WDSV) (5, 6, 18, 33, 39, 40, 44, 54, 63, 64, 71, 74). Germane to this review, the expression of cyclins D1, D2, and D3 from the bovine keratin-5 promoter (ker-5 p) induced a common mild skin hyperplasia but a variable cyclin-specific thymic hyperplasia in transgenic mice (63, 64). The distinct phenotypes of transgenic mice suggest that the three mammalian D-type cyclins are not fully redundant and that this system may be particularly suitable for analysis of novel cyclins that induce skin cell proliferation. Transgenic mice expressing the WDSV cyclin from the ker-5 p were recently analyzed (40). In contrast to the mild skin hyperplasia induced by human cyclin D1, D2, or D3 expressed from the same promoter, mice transgenic for the WDSV cyclin had a severe skin hyperplasia, hair loss, and morphological runting. Additionally, males had plugging of the accessory sex gland ductal system and females did not successfully nurse their first litter. Analogous to cyclin D3, the WDSV cyclin transgenic mice did not develop thymic hyperplasias. Presumably, the broad phenotype in these transgenic mice, including the severe disruption of normal skin proliferation, is due to biochemical properties of the WDSV cyclin (40). The WEHV rv-cyclins have not been tested for their ability to induce abnormal skin proliferation in transgenic mice. Collectively, these studies, in conjunction with viral gene expression studies, directly implicate the WDSV cyclin in the development of WDS and circumstantially implicate the WEHV rv-cyclins in WEH development. Interestingly, since very high levels of cyclin expression in some cells are associated with apoptosis (23, 24, 30, 37, 51, 52, 59, 77), it is possible that the epsilonretrovirus cyclins, analogous to cyclin D1, may induce cell proliferation or cell death (40, 41). Recently, it was reported that a WDSV amino-truncated Orf-A protein (the product of alternatively spliced mRNAs produced in regressing tumors), lacking its nuclear localization signal, did not enter the nucleus. These data led to the hypothesis that tumor development may be linked to the synthesis of the full-length rv-cyclin (containing the nuclear localization signal) and that regression may be linked to the synthesis of amino-truncated forms of the WDSV cyclin (67).


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POTENTIAL ROLES OF RV-CYCLINS IN THE VIRAL LIFE CYCLE
 
The WDSV, WEHV1, and WEHV2 rv-cyclins were likely captured from cellular cyclins but in the evolutionary past. The acquisition of a cyclin gene presumably provided these viruses with selective advantages because the cyclin gene stimulated cell division, thereby stimulating viral replication. Subsequently, the rv-cyclins may have evolved to specifically benefit viral replication, e.g., by the loss of inhibition by cellular regulatory proteins or by resistance to proteolysis. Alternatively, the derived rv-cyclins may interact with proteins with which cellular cyclins do not interact or only poorly interact, in order to stimulate cell proliferation and viral replication. This hypothesis is indirectly supported by the gammaherpesvirus v-cyclins, which have unique biochemical properties that may contribute to uncontrolled cell proliferation (15, 20, 28, 46, 72). In contrast to cellular cyclins, the KSHV v-cyclin in KSHV v-cyclin-Cdk6 complexes stimulates phosphorylation of pRb and also histone H1 (28), the KSHV v-cyclin-Cdk6 complex is resistant to inhibition by proteins that inhibit the cyclin D1-Cdk6 complex (72), and the KSHV v-cyclin-Cdk6 complex stimulates degradation of the p27Kip Cdk inhibitor (20, 46).

The role(s) of the divergent rv-cyclins in the viral life cycle and stimulation of cell proliferation may be multifaceted. For example, cyclins D and E activate Cdks, leading to the phosphorylation of pRb and to the G1-to-S transition, while cyclin A activates Cdk2, leading to the phosphorylation of the MDM2 protein, decreasing its ability to interact with and mark the tumor suppressor p53 for degradation (81). Additionally, cyclin D1, independently of Cdk interaction, activates the estrogen receptor transcription factor (84); D-type cyclins sequester the transcription factor DMP1 (84), thereby lowering cellular levels of the tumor suppressors p19Arf and p53 (34, 35); and cyclin T interacts with the Tat-TAR complex proteins to stimulate transcription of the human immunodeficiency virus genome (36, 55, 78, 83). More generally, cyclin C-Cdk8 complexes phosphorylate the C-terminal domain (CTD) tail of RNApol II, resulting in enhanced or repressed transcription from different cellular promoters (45, 73). Recently, it has been shown that the WDSV cyclin, like cellular cyclin C, interacts with Cdk8 and that this complex enhances or represses transcription from promoters by phosphorylation of the CTD tail of RNApol II (68). These data suggest that the WDSV cyclin, analogous to the accessory genes of other complex oncogenic retroviruses, may regulate the transcription of cellular genes that deregulate cell proliferation and promote cancer (1). It has been proposed that the full-length WDSV cyclin represses viral transcription through Cdk8 in developing tumors and may affect the transcription of cellular genes to promote cell proliferation (67, 68). It was also suggested that amino-truncated forms of the WDSV cyclin cannot enter the nucleus, thereby releasing repression of viral transcription in regressing tumors. There is no evidence from Northern blots or RT-PCR showing that mRNAs encoding amino-truncated forms of the WEHV rv-cyclins are produced in regressing WEH (42).

The interaction of the WDSV cyclin with Cdk8 is dependent on the long coiled-coil domain at its carboxy terminus distal to the cyclin box (Fig. 3) (68). A mutant WDSV cyclin that does not encode the coiled-coil domain did not interact with Cdk8 (Fig. 3). Interestingly, the WEHV rv-cyclins are smaller proteins that are not predicted to have an analogous coiled-coil domain. Therefore, they would not be predicted to affect viral or cellular gene expression through interaction with Cdk8. Supporting this hypothesis, the WDSV cyclin but not the WEHV rv-cyclins interacts with Cdk8 in glutathione transferase pull-down experiments (S.-W. Kim and D. Holzschu, unpublished data). These data suggest that, while the interaction of the WDSV cyclin with Cdk8 may play an important role in WDSV gene expression and the biology of WDS, the core ability of the rv-cyclins to induce cell proliferation is likely to be mediated by interactions with cellular proteins within the rv-cyclin box. In either case, we suggest that the rv-cyclins evolved to the benefit of their cognate viruses by stimulating cell proliferation.



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  		FIG. 3. The predicted structure of the rv-cyclins, derived from references 16 and 68. The taller vertical lines represent {alpha}-helices. L, the nuclear localizing leader domain; CB, the cyclin box; and CC, the coiled-coil region of the WDSV cyclin. WDSV-{Delta}, the protein produced from a DNA construct where a translational stop codon was inserted into the open reading frame at the beginning of the coiled-coil region (see text).


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FUTURE DIRECTIONS AND CONCLUSIONS
 
Analysis of the basic biology of the epsilonretroviruses awaits the development of a suitable tissue culture system for virus propagation. Being able to grow the viruses in tissue culture would allow many questions to be addressed, including (i) whether clones of WDSV and WEHVs fulfill Koch's postulates and induce WDS and WEH; (ii) what the contributions of the rv-cyclins, Orf-B, and Orf-C to viral gene regulation and replication are; (iii) if orf-C is translated, what the mechanism of translation of the downstream gag gene is; and (iv) what regulates the differences in the levels of viral gene expression and splicing patterns observed in developing and regressing WDS and WEH. Several attempts have been made to propagate WDSV in fish tissue culture cells (S. Quackenbush, personal communication) without success. In the absence of a suitable tissue culture system supporting viral propagation, the analysis of epsilonretroviruses will likely continue to be focused on biochemical properties of viral proteins, e.g., protease (PR), RT, and the rv-cyclins Orf-B and Orf-C. The biochemical properties of PR and RT may be particularly interesting, because the epsilonretroviruses are isolated from a poikilothermic host. For example, the RT of these viruses must be sufficiently active at approximately 4°C to establish infection. The WDSV PR and RT have been partially purified from virions and analyzed (21, 22). Interestingly, WDSV RT does not appear to be specifically adapted for activity at low temperatures, but like the RT isolated from northern pike lymphoma, it is temperature sensitive (57, 58). Sufficient WDSV RT was not purified to examine processivity and accuracy, necessitating the production of recombinant protein for study. While the rv-cyclins have received the most attention, the Orf-B and Orf-C proteins may be essential for viral replication and may contribute to tumor development and regression. Interestingly, Orf-C is more highly conserved among the epsilonretroviruses than are the Orf-As or Orf-Bs, suggesting that it may have an essential role in viral replication (42). The Orf-C protein has recently been shown to efficiently induce apoptosis (56). Therefore, Orf-C may play an important role in tumor regression. However, this implies that the production of virions and the induction of apoptosis must be coordinated in some manner, because orf-C, gag, and pol are all translated from full-length viral mRNA.

The discovery that the WDSV rv-cyclin interacts with Cdk8 to affect the processivity of RNApol II transcription, and therefore gene expression, is very important (68). It is likely that this discovery will contribute not only to the understanding of the biology of these unique retroviruses but will also contribute to the elucidation of the role(s) of cyclin-Cdk8 complex interaction with RNApolII in affecting transcription. Preliminary yeast two-hybrid analysis has identified cellular proteins that interact with the WDSV and WEHV2 rv-cyclins and can rationally be linked to gene expression and cell proliferation, suggesting alternative mechanisms that contribute to the oncogenic potential of the epsilonretroviruses (L. Yuan, S.-W. Kim, and D. Holzschu, unpublished data). The comparative biochemistry of the compendium of the rv-cyclins will likely lead to the understanding of structure/function differences that may be translated directly to their ability to induce cell proliferation and possibly provide clues to the genesis of WDS and WEH.

WDSV, WEHV1, and WEHV2 are the first examples of retroviruses that encode cyclin homologs, thus representing a new paradigm for the study of retrovirus-induced oncogenesis and cyclin-induced cell proliferation. While WDS and WEH are not the only seasonal tumors to be documented (seasonal tumors have been described in fish, frogs, and newts [3, 4, 25, 29, 53]), they are the only seasonal skin lesions for which the etiological agents have been cloned and sequenced. This tumor model system represents a unique venue for an integrative study of host and viral factors as they affect tumorigenesis and tumor regression. The rv-cyclins are highly divergent from cellular cyclins, making the investigation of their biochemical activities likely to have an impact on the present views of cellular cyclin roles in cell proliferation and cancer. Since the mechanisms responsible for WDS induction and regression are likely to have corollaries in homeothermic animals, investigation of the epsilonretroviruses will contribute not only to our basic understanding of cell cycle control but will also identify potential targets for pharmacological treatment of human tumors. Furthermore, characterization of these viruses will contribute to our understanding of retroviral biology, including viral replication, pathogenesis, and evolution.


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ACKNOWLEDGMENTS
 
We thank Volker Vogt and Sandra Quackenbush for contributing unpublished data and Linda Ross for her review of the manuscript.

This paper was partially supported by a grant from the Ohio Branch of the American Cancer Society to D.H.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Biological Sciences, 239 Life Sciences Bldg., Ohio University, Athens, OH 45701. Phone: (740) 593-0425. Fax: (740) 593-0300. E-mail: holzschu{at}ohiou.edu. Back


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Journal of Virology, December 2003, p. 12385-12391, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12385-12391.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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