Walleye dermal sarcoma virus

From MicrobeWiki, the student-edited microbiology resource
Revision as of 19:48, 15 October 2015 by BarichD (talk | contribs)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Jump to: navigation, search
This student page has not been curated.

A Viral Biorealm page on the species Walleye Dermal Sarcoma Virus (WDSV), Univ of Southern Maine

Baltimore Classification

Walleye Dermal Sarcoma Virus (WDSV) is a member of the family retroviridae that includes all exogenous retroviruses constituting Baltimore Classification Class VI. Class VI: Positive-sense single-stranded RNA viruses that replicate through a DNA intermediate.[1,2]

Higher Order Categories

Family: Retroviridae

Subfamily: Orthoretrovirinae

Genus: Epsilonretrovirus

WDSV is of the family retroviridae and belongs to the subfamily Orthoretrovirinae. Within that subfamily, WDSV is classified in the genus Epsilonretrovirus. The genus Epsilonretrovirus includes three species of piscine retroviruses, WDSV and walleye epidermal hyperplasia virus (WEHV) types I and II.[1,2]

Description and Significance

WDSV is the causative agent of Walleye Dermal Sarcoma, characterized by the seasonal growth and regression of skin tumors in the species.[3] The incidence of WDSV infection in various populations of sexually mature North American walleye (Sander vitreus) range from 1-30%.[4] Infection with WDSV and the formation of tumors is not a lethal condition for the infected organism.[1]

The value in studying WDSV is in the analysis of the viral genome and pathology of the disease. The study of one viral protein, rv-cyclin, enhances our current understanding of the regulation of the cell cycle in both normal and retrovirus-infected cells.[5,6] Understanding of the regulation of the cell cycle and malfunctions thereof is valuable to the study of all cancers.

Genome Structure

The genome of WDSV is a single-stranded, positive-sense RNA molecule 12,708 base pairs in length. 590 bp at either end of the genome are specified as long terminal repeat (LTR) regions which function to protect the coding genome from degradation and contains the initiation site for transcription.[7] The LTR also contains binding sites for transcription factors, such as AF-1, AF-3, NF-κB, which regulate the frequency of transcription and therefore the course of the viral replication cycle.[7,8]

Downstream from the LTR is the first of three open reading frame (ORF) regions of the viral genome, this one designated orf-C.7 Orf C protein is encoded by the full-length, genomic transcript, and expression is only observed in the springtime period of tumor regression.[3] Orf C protein is found to colocalize with mitochondria, correlating with a loss of the normal cytoplasmic localization of the mitochondria. Cells induced to transiently express Orf C exhibited apoptotic morphology, implying a functional role for WDSV Orf C in an alteration of mitochondrial function that results in apoptosis contributing to tumor regression.[9]

Next is the gag gene, which codes for several important internal virion structures, including the capsid (CA) and nucleocapsid (NC) proteins.[7,10] Next, the pro and pol gene sequences which code for viral enzymes protease (PR, which is responsible for cleaving the polyproteins that result from translation of multi-gene transcripts), reverse transcriptase (RT, which is responsible for transcribing a double-stranded DNA copy of the viral genome), and integrase (IN, which is responsible for integrating the dsDNA viral genome into the host genome).[7,11] Following the pol gene is the env gene, which codes for the Env polyprotein. The Env polyprotein is cleaved in the Golgi apparati of host cells into surface (SU) and transmembrane (TM) protein components of the viral envelope.[11]

Downstream from the env gene are two open reading frame (ORF) genes, orf-A and orf-B. Experimental evidence has revealed that full-length Orf A is the predominant transcript in developing, but not regressing, tumors. The gene codes for a retroviral cyclin homologue (rv-cyclin).[7,11] Cyclins are a family of proteins that are found to control the cell cycle through their interaction with cyclin-dependent kinases. Cyclins are named because their expression varies in a cyclical fashion during the cell cycle. The rv-cyclin has homology eukaryotic D-type and A-type cyclins, which are responsible for the transition from the G1 phase to S phase and maintenance of S-phase, respectively. As such, rv-cyclin expression is critical to the proliferative replication that typifies the formation of tumors.[5,6]

The orf-B gene codes for the 306 amino acid protein Orf B, which localizes in the cytoplasm and at the cell membrane in tumor cells.[7,11,12] Orf B has been shown to interact with the protein receptor for activated C kinase (RACK1). RACK1 binds to some activated isoforms of protein kinase C (PKC), stabilizing PKC at the membrane in an active conformation.[12] The PKC signaling pathway regulates essential processes, including cell proliferation, differentiation, survival and apoptosis. Experimental evidence from Orf B-expressing cells suggests that interaction of Orf B with RACK1 and a constitutively active PKCα isoform. The activation of the PKC signaling pathway in Orf B-expressing cells confers an ability to survive and proliferate.[12]

Virion Structure

To date, no extensive characterization of WDSV or any member of the Epsilonretrovirus genus has been performed. Due to the great deal of genomic similarity between WDSV structural components (primarily the env gene)[4,7] and those of other retroviruses, one might cautiously assume that the structure of the virion particles are conserved between the different species.

The envelope of retroviruses is the most external structure, and is composed of host plasma membrane lipids and env gene-encoded glycoproteins. The envelope functions to protect the viral genome and facilitates attachment and entry into host cells.[7,10,11]

Interior to the envelope, the viral capsid, which encapsulates the viral genome. The capsid is formed by protein derivatives of the gag gene, which self-assemble to form a protective shell. The viral genome consists of two identical copies of dimerized, positive-sense, single-stranded RNA molecules, each 12,708 base pairs in length.[7] The capsid must also contain active copies of the protease, reverse transcriptase, and integrase proteins that are essential for successful replication.

Reproductive Cycle in a Host Cell

WDSV is characterized by a seasonal progression and regression of dermal sarcoma tumors. This progression and regression is a result of the reproductive cycle of WDSV within the host.[1]

Upon infection, the viral genome is reverse-transcribed into double-stranded DNA by the viral reverse transcriptase protein.[7] The dsDNA copy of the viral genome is incorporated into the host genome by the viral integrase protein and the viral reproductive cycle enters the latent, or lysogenic, phase. During the late summer and early autumn, host cells begin to express low levels of Orf A and B gene transcripts through an unknown mechanism, which is concurrent with the development of the dermal sarcoma tumors to which WDSV is etiologically linked.[1,13] The primary products of these genes, such as rv-cyclin, promote proliferative replication of viral-infected cells and as such are likely the cause of tumor formation and proliferation. During this phase, low levels of virus formation are observed, likely due to the inhibition of the viral promoter by rv-cyclin localized in the nucleus.[6]

Tumor regression is marked by widespread apoptosis of host cells and the formation of large numbers of viral particles.[1] Tumor regression coincides with walleye spawning in early spring, conferring a high likelihood of infectious transfer to previously uninfected individuals. During this phase, transcription of the entire viral genome is high, a necessary event for the production of large numbers of infectious viral particles. The expression of high levels of Orf C protein has been implicated in the induction of the apoptotic phenotype in host cells due to disruption of normal mitochondrial function.[9]

Viral Ecology & Pathology

WDSV infection occurs at variable frequency between different populations of Sander vitreus, which is native to fresh water bodies in most of Canada and the eastern United States. The highest recorded incidence of walleye dermal sarcoma is in Oneida Lake in New York state, where an estimated 30% of the sampled population have the tumors. Other sampled populations from surrounding areas reveal the prevalence of the diseased phenotype to be in the order of 1%.[1,2,3]

WDSV infection is postulated to occur primarily during the spring-time spawning season, when tumor regression and high rates of viral replication are also recorded. Physical contact during spawning is likely the most efficient means of the transfer of virus from an infected individual to a previously uninfected one.[13]

The formation of walleye dermal sarcomas is the only known symptom of infection. The sarcoma tumors are not a terminal condition for the fish. Moreover, tumors have not been observed to recur in previously-infected individuals.[1]

References

1. Holzschu, D., L. A. Lapierre, and M. D. Lairmore (2003) Comparative Pathogenesis of Epsilonretroviruses, Journal of Virology 77.23: 12385-2391; doi/10.1128/​JVI.77.23.12385-12391.2003

2. Zhang, Z (1996) Phylogenetic and Epidemiologic Analysis of the Walleye Dermal Sarcoma Virus, Virology 225.2: 406-12; doi/10.1006/viro.1996.0616

3. Bowser, P. R., Wooster, G. A., Quackenbush, S. L., Casey, R. N. & Casey, J. W. (1996) Comparison of fall and spring tumors as inoculation for experimental transmission of walleye dermal sarcoma, Journal of Aquatic Animal Health 8: 78–81; doi/10.1577/1548-8667(1996)008<0078:CCOFAS>2.3.CO;2

4. Holzschu, D.L. (1997) Molecular Characterization of a Piscine Retrovirus, Walleye Dermal Sarcoma Virus, Leukemia 11: 172-75; doi/N/A. PMID:9209334


5. Rovnak, J., Casey, J.W., Quackenbush, S.L. (2001) Intracellular Targeting of Walleye Dermal Sarcoma Virus Orf A (rv-Cyclin), Virology 280: 31-40; doi/10.1006/viro.2000.0731

6. Rovnak, J., Hronek, B.W., et al. (2005) An activation domain within the walleye dermal sarcoma virus retroviral cyclin protein is essential for inhibition of the viral promoter, Virology 342: 240 – 251; doi/10.1016/j.virol.2005.08.011

7. Holzschu, Donald L. (1995) Nucleotide Sequence and Protein Analysis of a Complex Piscine Retrovirus, Walleye Dermal Sarcoma Virus, Journal of Virology 69.9: 5320-331; doi/N/A. PMID:7636975

8. Quackenbush, S.L., Linton, A., et al (2009) Walleye Dermal Sarcoma Virus Rv-cyclin Inhibits NF-kB Dependent Transcription Virology. 386(1): 55–60; doi/10.1016/j.virol.2008.12.026

9. Nudson, Wade A. (2003) Walleye Dermal Sarcoma Virus Orf C Is Targeted to the Mitochondria, Journal of General Virology 84: 375-81; doi/10.1099/vir.0.18570-0

10. Rovnak, J., Quackenbush, S.L. (2010) Walleye Dermal Sarcoma Virus: Molecular Biology and Oncogenesis, Viruses 2: 1984-1999; doi/10.3390/v2091984

11. Quackenbush, S.L., Holzschu, D.L., et al. (1997) Transcriptional Analysis of Walleye Dermal Sarcoma Virus (WDSV), Virology 237: 107–112; doi/N/A. PMID:9344912

12. Candelaria, D.C., Rovnak, J., Quackenbush, S.L. (2008) Walleye Dermal Sarcoma Virus Orf B Functions through Receptor for Activated C Kinase (RACK1) and Protein Kinase C, Virology 375.2: 550–560; doi/10.1016/j.virol.2008.01.034

13. Rovnak, J., Casey, R.N., et al. (2007) Establishment of productively infected walleye dermal sarcoma explant cells, Journal of General Virology 88: 2583–2589; doi/10.1099/vir.0.82967-0