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Introduction edit
Yaba monkey tumor virus (YMTV) is a virus in the family Poxviridae, the subfamily Chordopoxvirinae, and the genus Yatapoxvirus. The species name is Yaba Monkey Tumor Virus.[1] Electron microscopy was used to confirm the similarity between YMTV and other poxviruses, such as Vaccinia virus (VACV).[2] Similar to other yatapoxviruses, YMTV is a large, complex virus that replicates in the cell cytoplasm and encodes enzymes for transcription and replication. YMTV has a double stranded DNA genome that is greater than 134kb [2]. Additionally, the DNA has G+C amino acid content of 32.5%. [3]
Yaba monkey tumor virus was first discovered in 1957 by researchers working in Yaba, Lagos, Nigeria. The virus was recovered from cutaneous tumors in a colony of rhesus monkeys (Mucaca mulatta)[2]. The virus name stems from a combination of the place of origin and Pox, the English word for pock or pustule, referring to the ability to form skin lesions in primates. The tumors produced by YMTV after subcutaneous or intradermal inoculation produce benign histiocytomas in the skin that spontaneously resolve in 1-2months [2] [3]. The tumors are composed of masses of histiocytes, which later become infiltrated with lymphocytes and polymorphonuclear cells. No true neoplastic proliferation occurs, and the lesions eventually regress as the immune response expands [3].
The natural hosts for YMTV are Asiatic monkeys (Mucaca mulatta, Mucaca irus, and Mucaca speciosa). African monkeys (Cercopithecus aeth- iops, Cercopithecus mona, and Cercopithecus fuliginosus) from West and Central Africa, as well as humans, are susceptible to the virus [2]. YMTV is transmitted through direct contact or vector transmission by insects. Thus far, there are no known vaccines or antiviral drugs to combat the Yaba monkey tumor virus [1].
Viral Classification edit
YMTV belongs to the genus Yatapoxvirus, which belongs to Chordopoxvirinae, a subfamily of Poxviridae. Chordopoxvirinae members are characterized by their infection of vertebrates [3]. All poxviridae members adhere to three primary characteristics: (1) an enveloped genome encapsulating mRNA enzymes, (2) 130 to 300 kbp linear dsDNA genome, and (3) cytoplasmic replication [3]. Yatapoxvirus contains two species, YMTV and Tanapox virus (TANV), which are closely related [4]. A third virus, Yaba-like disease virus (YLDV), also belongs to the Yatapox genus but is so closely related to TANV that it is considered to be a strain of the TANV species.[4]
Structure edit
YMTV virus particles are very large in size, approximately 300x250x200nm, and have an elongated brick shape. There are two distinct types of mature infectious virus particles: intracellular mature virion (IMV) and extracellular enveloped virus (EEV). [1]The mature virions (MV) are surrounded with a lipid bi-layer membrane containing surface tubules and more than a dozen viral proteins. Extracellular virus particles undergo additional membrane wrapping, which forms an envelope covered with glycoproteins.[5] The virus particles contain a dumbbell shaped core composed of tightly packed nucleoproteins consisting of genomic dsDNA, and have two lateral bodies. Early, immature forms of the virus are more circular in shape and do not contain a core or envelope. They do, however, feature radially oriented spines on their surface, which has not been seen in other poxviruses.[6]
Genome edit
YMTV is a member of the Yatapox genus of the poxviruses, along with Yaba-like disease virus (YLDV) and Tanapox virus (TPV). YMTV has a linear, dsDNA genome of about 135kb, which makes it the smallest poxvirus genome sequenced. It has an A+T makeup of 70.2% and encodes for 140 open reading frames (ORFs); 13 fewer than what is present in YLDV. The linear genome contains inverted terminal repeats (ITRs) that are 1,962 bases long. The ITRs contain one ORF that is specified as 1L/151R and a non-coding region of about 800 bases. The non-coding region of YMTV does not have a methionine initiator codon (ATG), which may suggest that it has evolved into a psuedogene.[4]
Replication Cycle edit
To initiate cell entry, and thus replication, viral proteins attach to host glycosaminoglycans (GAGs), which induces endocytosis of the virus into the host cell. [1] The envelope then fuses with the plasma membrane and the core is released into the cytoplasm of the host cell.
During the early phase of infection, the core starts to uncoat. Before the uncoating process is finished, the early genes are transcribed in the cytoplasm by viral copies of RNA polymerase. [1] Replication reaches its highest rate around 18 hours post-infection and continues for the next 2 or 3 days, depending on infection multiplicity and the type of host cell. [2] Expression of early genes begins 30 minutes after infection, and by the time the expression of early genes is finished, the core is entirely uncoated and the genome is free in the cytoplasm.
At 100 minutes post-infection, intermediate genes are expressed, which triggers virus genomic DNA replication. Interestingly, viral DNA is resistant to host DNAase. [2] From 140 minutes post-infection on, late genes are expressed. Late genes include all structural proteins. [1] Progeny virions are then assembled in viral factories, which are intracellular inclusions that increase efficiency of assembly and protect from host defenses. [1] These factories are formed of cylindrical subunits and are distributed throughout the cell. [6]
The virion produced in the factories is a spherical immature particle, which then matures into a rectangular intracellular mature virion (IMV). [1] Near the end of the maturation process, an outer double membrane is assembled from materials in the surrounding cytoplasm. [6] The IMV can then either be released upon cell lysis or can obtain another double membrane from the trans-Golgi network and then bud as an external enveloped virion (EEV). [1] The produced virion is then ready to go on and infect other cells.
Host Interaction and Response edit
The poxviral E3 ubiquitin-protein ligase LAP of YMTV inhibits the adaptive immune response. This is done by promoting the ubiquitination and the subsequent degradation of host MHC class I molecules and CD4 glycoproteins [1]. The degradation of these molecules inhibits the immune response, allowing for the continued replication of the virus.
Yatapoxviruses encode a distinct class of TNF-binding proteins that resemble an MHC class I heavy chain. TNFs are secreted primarily by macrophages and monocytes, which play critical roles in the innate immune response. TNFs are potent mediator cytokines that induce inflammation and the immune response to various pathogens. The viral TNFs are distinct from any other known TNF inhibitors, and are important in suppressing the immune response. The Yaba monkey tumor virus 2L protein (YMTV-2L) inhibits the human TNF-mediated signaling in cells.[7]
The extracellular bioactivity of the proinflammatory cytokine Interleukin-18 (IL-18) is regulated by a cellular IL-18 binding protein (IL-18BR). The YMTV genome encodes a IL-18BR family member, 14L. YMTV 14L binds both the human Il-18 (hIL-18) and the murine IL-18 with high affinity. YMTV 14L is able to fully sequester hIL-18, but only partially inhibits the biological activity of soluble hIL-18 ligand. This suggests that YMTV 14L functions more to sequester the host cytokine than to directly inhibit the IL-18 signaling pathway through its rector. In this way, Il-18 is prevented from reaching its target cellular receptors. This different inhibition mechanism may be attributed to the modified binding specificity in comparison to other poxviral IL-18BPs.[8]
Pathology/Pathogenesis edit
YMTV, as the name suggests, is a tumor-producing dsDNA poxvirus. Upon infection, the formation of tumor-like masses, called histiocytomas, is induced [3]. Histiocytomas are benign masses, or skin lesions, made up of histiocytes, or mononuclear cells, that most commonly form on the head and extremities [2]. These skin lesions gradually form within 7 to 10 days post-infection, reaching a size of 4 to 5 centimeters in diameter [2]. YMTV is unique in that it targets histiocytes, as opposed to epithelial cells, which are the target of other Poxviridae members [9] , and it differs from TANV in that it is proliferative and infects the mesodermal layer whereas TANV is restricted to infection of the epidermis [2]. The histiocytomas will spontaneously regress within 3 months of their onset [2].
YMTV is a zoonotic virus that is transmitted either by direct contact or via mosquitoes and other biting insects [1]. It became known that it can infect and result in tumor formation in humans after an incident in a lab, where an accidental infection of humans resulted from a needle puncture [2]. While it can infect humans in the wild, there have been no reported infections outside of a laboratory.
References edit
- ^ a b c d e f g h i j k "ViralZone: Yatapoxvirus." ViralZone: Yatapoxvirus. SIB Swiss Institute of Bioinformatics, n.d. Web. 06 Dec. 2014.
- ^ a b c d e f g h i j k l Mercer, A. A., Axel Schmidt, and Olaf F. Weber. "Genus Yatapoxvirus." Poxviruses. Basel: Birkhäuser, 2007. 113-25. Print.
- ^ a b c d e f Fields, Bernard N., M.D., and David M. Knipe, Ph.D. "Chapter 75/ Tanapox and Yaba Monkey Tumor Poxvirus Infections." Fields Virology. 2nd ed. Vol. 2. New York: Raven, 1990. 2128-129. Print.
- ^ a b c Brunetti, Craig R., Hiroko Amano, Yoshiaki Ueda, Jing Qin, Tatsuo Miyamura, Tetsuro Suzuki, Xing Li, John W. Barrett, and Grant McFadden. "Complete Genomic Sequence and Comparative Analysis of the Tumorigenic Poxvirus Yaba Monkey Tumor Virus." Journal of Virology 77.24 (2003): 13335-3347. Web.
- ^ Upton, C., and G. Mcfadden. "Tumorigenic Poxviruses: Analysis of Viral DNA Sequences Implicated in the Tumorigenicity of Shope Fibroma Virus and Malignant Rabbit Virus." Virology 152.2 (1986): 308-21.Elsevier. Web. 6 Dec. 2014.
- ^ a b c Harven, Etienne De, and David S. Yohn. "The Fine Structure of the Yaba Monkey Tumor Poxvirus." Cancer Research 26 (1966): 995-1008.AACR Journals. Web. 6 Dec. 2014.
- ^ Rahman, M. M. "Variation in Ligand Binding Specificities of a Novel Class of Poxvirus-encoded Tumor Necrosis Factor-binding Protein." Journal of Biological Chemistry 281.32 (2006): 22517-2526. Web.
- ^ Nazarian, S. H., M. M. Rahman, S. J. Werden, D. Villeneuve, X. Meng, C. Brunetti, C. Valeriano, C. Wong, R. Singh, J. W. Barrett, Y. Xiang, and G. Mcfadden. "Yaba Monkey Tumor Virus Encodes a Functional Inhibitor of Interleukin-18." Journal of Virology 82.1 (2007): 522-28. Web.
- ^ "Yaba Pox Virus." - Exotic. The University of Sydney Centre for Veterinary Education, n.d. Web. 06 Dec. 2014.
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