Mason pfizer monkey virus: Difference between revisions

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==Classification==
==ICTV Classification==


===Higher order taxa===
===Higher order taxa===


Viruses; Retro-transcribing viruses; Retroviridae; Orthoretrovirinae; Betaretrovirus [http://www.ncbi.nlm.nih.gov/Taxonomy/ NCBI]
Viruses; Retro-transcribing viruses; Retroviridae; Orthoretrovirinae; Betaretrovirus [http://www.ncbi.nlm.nih.gov/Taxonomy/NCBI- (Chappy, C., 1997, Petropoulos, C.J., 1997)].


===Species===
===Species===


''Genus species'': Mason Pfizer Monkey Virus
''Genus species'': Mason Pfizer Monkey Virus [http://www.ncbi.nlm.nih.gov/Taxonomy/NCBI- (Chappy, C., 1997, Petropoulos, C.J., 1997)].
{|
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'''NCBI: [http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Tree&id=2&lvl=3&lin=f&keep=1&srchmode=1&unlock Taxonomy]'''
|}


==Description and significance==
==Description and significance==


Mason Pfizer Monkey virus (MPMV)is a simian type-D retrovirus (SRV)and is the most thoroughly understood of the D-type betaretroviruses. MPMV is the prototype of the type-D retroviruses. The fundamental assembly steps(Gag particle formation, transport to the membrane, membrane interaction/viral budding, and viral release) are separate sequential processes allowing this virus to serve as an important model of retroviral assembly (Parker and Hunter, 2001). MPMV was first observed by Harish C. Chopra and Marcus M. Mason in 1970 from a spontaneous breast carcinoma in an 8-year old rhesus monkey (Macaca mulatta)(Chopra and Mason, 1970). MPMV is a primate retrovirus which has properties similar to the C-type and B-type viruses, but is morphologically distinct (Fine and Schochetman, 1978). MPMV is also distinguished by accumulation of A-type intracellular particle accumulation and budding release. MPMV is pathogenic in old world monkeys(Cercopithecidae)(Fine and Schochetman, 1978) causing immunodeficiency syndrome (Bohl et al., 2005) and tumors (Heras et al., 1991).
Mason Pfizer Monkey virus (MPMV) is a simian retrovirus (SRV), as well as the most thoroughly understood of the D-type Betaretrovirus. MPMV is the prototype for the D-type retroviruses. The fundamental assembly steps (gag particle formation, transport to the membrane, membrane interaction/viral budding, and viral release) are separate sequential processes allowing this virus to serve as an important model of retroviral assembly (Parker and Hunter, 2001). MPMV was first observed by Harish C. Chopra and Marcus M. Mason in 1970 from a spontaneous breast adenocarcinoma in an 8-year old rhesus monkey (Macaca mulatta) that had been in estrus for approximately one year (Chopra and Mason, 1970). MPMV has properties similar to the C-type and B-type viruses but is morphologically distinct (Fine and Schochetman, 1978), which initially designated the virus into the genus Oncornavirus D. However, after further characterization of the virus, the recent taxonomic genus classification has been changed to Betaretrovirus. MPMV is distinguished by accumulation of A-type intracellular particles in the cytoplasm and budding release to acquire viral protease activity. MPMV is pathogenic in Old World monkeys, Family Cercopithecidae (Fine and Schochetman, 1978) and causes immunodeficiency syndrome (Bohl et al., 2005) and tumors (De las Heras et al., 1991).
 
Initially the classification of the virus was based on the idea the virus induced simian AIDS (SAIDS), however, it is now known that SRVs are unrelated to simian immunodeficiency virus (SIV), which is currently recognized as the simian counterpart of the human immunodeficiency virus (Conte et al., 1997).


==Genome structure==
==Genome structure==


MPMV genome is dimeric; not segmented, and consists of a single molecule of linear, positive-sense single-stranded RNA. The genome has been fully sequenced and the complete genome is of one monomer of 8,557 nucleotides in length.  The genome has terminally redundant sequences that have long terminal repeats (LTR) of about 350 nucleotides. The 5'–end of the genome has a methylated nucleotide cap; cap sequence type is of type 1 m7G5ppp5'GmpNp. The 3'–terminus has of each monomer a poly (A) tract. The 3'–terminus has a tRNA–like structure, and accepts lysin. http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/
MPMV genome is dimeric, not segmented, and consists of a single molecule of linear, positive-sense, single-stranded RNA. The genome has been fully sequenced and the complete genome is of one monomer of 8,557 nucleotides in length.  The genome has terminally redundant sequences that have long terminal repeats (LTR) of about 350 nucleotides. The 5'–end of the genome has a methylated nucleotide cap; cap sequence is of type 1 m7G5ppp5'GmpNp. The 3'–terminus of each monomer has a poly (A) tract, a tRNA–like structure, and accepts lysin. [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/ - ICTVdB - The Universal Virus Database, version 4.]


Proteins constitute about 60% of the particle weight. The viral genome encodes structural proteins and non-structural proteins, with the non-structural proteins coding for an RNA-dependent DNA polymerase. http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/
The genome contains four protein coding genes, and two non protein coding genes.
The genome contains four protein coding genes, and two non protein coding genes.
gag-pro-pol-env genes (MPMVgp1) code for protein products: Pr95, DU, RT-IN, gp70 SU, gp20 TM, and p12 PR. NC_001550. gag gene (MPMVgp2) codes for protein products: Pr78, p14 NC, p10 MA, p24, p12, and p 27. NC_001550. Non-protein coding genes are pro, (MPMVgp3) and pol, (MPMVgp4). NC_001550
gag-pro-pol-env genes (MPMVgp1) code for protein products: Pr95, DU, RT-IN, gp70 SU, gp20 TM, and p12 PR. The gag gene (MPMVgp2) codes for protein products: Pr78, p14 NC, p10 MA, p24, p12, and p 27. Non-protein coding genes are pro, (MPMVgp3) and pol, (MPMVgp4) [http://www.ncbi.nlm.nih.gov/Taxonomy/NCBI - (Chappy, C., 1997, Petropoulos, C.J., 1997)].


Lipids are present and located in the envelope. The virions are composed of 35% lipids by weight. The composition of viral lipids and host cell membranes are similar. The lipids are of host origin and are derived from plasma membranes.http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/
==Virion Structure==
MPMV consists of an envelope, a nucleocapsid, and a nucleoid. Virus capsid (core) is enveloped. Proteins constitute about 60% of the particle weight. The viral genome encodes structural proteins and non-structural proteins, in which the non-structural proteins code for an RNA-dependent DNA polymerase. Lipids are present and located in the envelope, and the virus is composed of 35% lipids by weight. The composition of viral lipids and host cell membranes are similar. The lipids are of host origin and are derived from plasma membranes [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/ - ICTVdB - The Universal Virus Database, version 4.].


==Virion Structure==
Two types of particles classify MPMV.  A-type particles are intracytoplasmic,electron-dense, ring-shaped particles measuring about 70 mµ in diameter. These immature particles pre-assemble in the cytoplasm and may occur singly or in cluster (Mason, 1970). Fully formed immature particles subsequently migrate to the plasma membrane where envelopment and budding occur at the cell surface (Sakalian et al., 2002). Upon release, nascent immature particles undergo a maturation process to acquire infectivity (Bohl et al., 2005). These mature extracellular particles are composed of a well defined spherical oval membrane and a central dense nucleoid  measuring about 110 mµ in diameter. The mature particles are connected to or very close the plasma membrane (Chopra and Mason, 1970).


Two types of particles compose MPMV.  A-type particles are intracytoplasmic,electron-dense, ring-shaped particles measuring about 70 m/u in diameter. These immature particles pre-assemble in the cytoplasm and may occur singly or in cluster (Mason, 1970). Fully formed immature particles subsequently migrate to the plasma membrane where envelopment and budding occur at the cell surface (Sakalian et al., 2002). Upon release, nascent immature particles undergo a maturation process to acquire infectivity (Bohl et al., 2005). These mature extracellular particles are composed of a well defined spherical oval membrane and a central dense nucleoid  measuring about 110 m/n in diameter. The mature particles are connected to or very close the plasma membrane (Mason, 1970).


MPMV contains unique D-type morphology, similar yet distinguished morphology from type-C and type-B retrovirus. Less dense knob shaped surface spikes, cylindrical capsids, and tubular nucleoid region.  
MPMV contains unique D-type morphology, similar yet distinguished morphology from type-C and type-B retrovirus. Less dense knob shaped surface spikes on the envelope, cylindrical capsids (Bohl et.al., 2005), size of intracytoplasmic A-type particles, and eccentric nucleoid region (Fine and Schochetman, 1978) distinguishes MPMV as a D-type Betaretrovirus.


==Ecology==


Virions{ }; have a complex construction; { } and consist of an envelope, a nucleocapsid, and a nucleoid. Virus capsid (core) is enveloped. Virions are spherical to pleomorphic; measure    80–100 nm in diameter. The surface projections are small { }; { } spikes { }; { } evenly covering the surface. They are { } densely dispersed. The core is spherical. The nucleoid is eccentric. http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/
Mason Pfizer monkey virus was first isolated from mammary breast adenocarcinoma and infects a single type of vertebrate host during its life cycle. Viral hosts belong to the Domain Eucarya, Kingdom Animalia, Phylum Chordata, Subphylum Vertebrata, Class Mammalia, Order Primates [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/ - ICTVdB - The Universal Virus Database, version 4.]


==Ecology==
Exogenous and endogenous D-type viruses infect a variety of mammalian hosts including New World monkeys, (squirrel monkey retrovirus [SMRV]), sheep (Jaagsiekte sheep retroviruss), goat (enzootic nasal tumor virus), as well as D-type virus sequences isolated from humans (Bohl et al., 2005).
Habitat; symbiosis; contributions to the environment.


Mason Pfizer monkey virus was first isolated from mammary breast carcinoma in rhesus monkey, and old world monkey. Virus isolates maintain infectious in other old world monkeys such as langur monkeys, new world monkeys, as well as isolate type D retroviruses from humans; this retrovirus infects
With direct hybridization of radioactive MPMV 70S RNA to DNA of various animal species, it has been shown that a portion(approximately 20%) of the MPMV genome was present in the cellular DNA of several Old World monkeys of the subfamily Cercopithecinae. No sequence homology was observed between MPMV and the cellular DNA's of New World monkeys, apes (including man), and several non-primates (Fine and Schochetman, 1978) indicating pathogenicity of MPMV occurs only in Old World monkeys.
rhesus monkeys body temperature 36-40 degrees C Human 36.9. This slight fluctuation of temperature indicates this virus requires mesophillic conditions (15 and 40 °C)in a host.


==Pathology==
==Pathology==
How does this organism cause disease?  Human, animal, plant hosts?  Virulence factors, as well as patient symptoms.


Requires host cells for metabolism
By itself, genomic nucleic acid of MPMV is not infectious. Viral protease activity is strictly limited to the completion of the viral budding process (Parker and Hunter, 2001).  
Retroviral aspartyl protease. Single domain aspartyl proteases from retroviruses, retrotransposons, and badnaviruses (plant dsDNA viruses). These proteases are generally part of a larger polyprotein; usually pol, more rarely gag. Retroviral proteases appear to be homologous to a single domain of the two-domain eukaryotic aspartyl proteases such as pepsins, cathepsins, and renins (pfam00026)-Marchler-Bauer A, Anderson JB, Derbyshire MK, DeWeese-Scott C, Gonzales NR, Gwadz M, Hao L, He S, Hurwitz DI, Jackson JD, Ke Z, Krylov D, Lanczycki CJ, Liebert CA, Liu C, Lu F, Lu S, Marchler GH, Mullokandov M, Song JS, Thanki N, Yamashita RA, Yin JJ, Zhang D, Bryant SH. (2007) CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res. 35: D237-40


RnaseH; RNase H. RNase H digests the RNA strand of an RNA/DNA hybrid. Important enzyme in retroviral replication cycle, and often found as a domain associated with reverse transcriptases. Structure is a mixed alpha+beta fold with three a/b/a layers. -Marchler-Bauer A, Anderson JB, Derbyshire MK, DeWeese-Scott C, Gonzales NR, Gwadz M, Hao L, He S, Hurwitz DI, Jackson JD, Ke Z, Krylov D, Lanczycki CJ, Liebert CA, Liu C, Lu F, Lu S, Marchler GH, Mullokandov M, Song JS, Thanki N, Yamashita RA, Yin JJ, Zhang D, Bryant SH. (2007) CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res. 35: D237-40
Reverse transcriptases (RTs) catalyze the conversion of single-stranded RNA into double-stranded viral DNA for integration into host chromosomes. Proteins in this subfamily contain long terminal repeats (LTRs) and are multifunctional enzymes with RNA-directed DNA polymerase, DNA directed DNA polymerase, and ribonuclease hybrid (RNase H) activities. The viral RNA genome enters the cytoplasm as part of a nucleoprotein complex, and the process of reverse transcription generates in the cytoplasm forming a linear DNA duplex via an intricate series of steps. This duplex DNA is collinear with its RNA template, but contains terminal duplications known as LTRs that are not present in viral RNA. It has been proposed that two specialized template switches, known as strand-transfer reactions or "jumps", are required to generate the LTRs [http://www.ncbi.nlm.nih.gov/pubmed/9831551?dopt=Abstract - (Huang et al., 1998)].


Integrase Zinc binding domain. Integrase mediates integration of a DNA copy of the viral genome into the host chromosome. Integrase is composed of three domains. This domain is the amino-terminal domain zinc binding domain. The central domain is the catalytic domain pfam00665. The carboxyl terminal domain is a DNA binding domain pfam00552.
Infection by retroviruses is associated with immune cell dysfunction. MPMV induces a fatal immunodeficiency syndrome in rhesus macaques (Conte et al., 1997). Newborn rhesus monkeys experimentally inoculated with MPMV developed a wasting disease within a few weeks accompanied by opportunistic infections including pneumonia, enteritis and rashes. Macaques naturally infected in primate centers and zoos die from opportunistic infections. While the virus was widespread, post-mortem examination revealed only lymphadenopathy and thymic atrophy. The opportunistic infections as a thymic target supports the virus exerts a T-cell immunosuppressive effect, as has been suggested for other D-type retroviruses (Fine et al., 1975.)
PMID: 9228950
Induces fatal immune suppression by attacking T-lymphocyte cells in mammalian hosts.  
Newborns treated with MPMV -
Older monkeys with MPMV-


Integrase DNA binding domain. Integrase mediates integration of a DNA copy of the viral genome into the host chromosome. Integrase is composed of three domains. The amino-terminal domain is a zinc binding domain. The central domain is the catalytic domain pfam00665. This domain is the carboxyl terminal domain that is a non-specific DNA binding domain. PMID: 7632683
The MPMV envelope has been shown to have an immunosuppressive effect in vivo by using an assay involving rejection of tumor cells in immuno-competent mice. The experimental results also support an initiation of T-cell response with MPMV infection. The immunosuppressive properties of MPMV does not function based solely on a well conserved domain of 17 amino acids located within the transmembrane subunit of retroviral envelopes, but several domains within the envelope protein, and may be dependent on the overall structure of the protein (Blaise et al., 2001).


Pr95 -
==Current Research==
MPMV is an important model to study human disease, and can be used experimentally as a tool to find potential inhibitors of HIV immature particle assembly. In an experiment by Sakalian and coworkers (2002), Assembly of HIV gag was enabled with regions of MPMV gag inserted into the HIV gag to create chimeric gag molecules. These chimeras were capable of assembly into immature capsid-like structures in vitro. Chimeric species containing large regions of MPMV gag fused to HIV gag failed to assemble. Species consisting of only the MPMV p12 region and its internal scaffold domain (ISD) fused to HIV gag were capable of assembly, however at reduced kinetics compared to the MPMV gag. The ISDs ability to induce assembly of the HIV gag in the plasma membrane, proposes a common requirement for a concentrating factor in retrovirus assembly.  The function of the HIV gag domain remained essential, as confirmed by an assembly-defective mutant of HIV CA, M185A, that abolished assembly when introduced into the chimera. The continued requirement for HIV gag domain function in the assembly of chimeric molecules will allow in vitro systems to be used for analysis of potential inhibitors of HIV immature particle assembly (Sakalian et al., 2002).


gp20 TM - ENV polyprotein (coat polyprotein).  - Marchler-Bauer A, Anderson JB, Derbyshire MK, DeWeese-Scott C, Gonzales NR, Gwadz M, Hao L, He S, Hurwitz DI, Jackson JD, Ke Z, Krylov D, Lanczycki CJ, Liebert CA, Liu C, Lu F, Lu S, Marchler GH, Mullokandov M, Song JS, Thanki N, Yamashita RA, Yin JJ, Zhang D, Bryant SH. (2007) CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res. 35: D237-40
                                                                                         
- gag gene protein p24 (core nucleocapsid protein). p24 forms inner protein layer of the nucleocapsid. ELISA tests for p24 is the most commonly used method to demonstrate virus replication both in vivo and in vitro. PMID: 9245608
                                                                                          [[Image:Complete labeled image.JPG|right]]
MPMV is also an effective tool for gene therapy. Novel vectors are capable
of producing MPMV proteins but not packaging MPMV RNA, and the information
about the packaging signal in MPMV and HIV can be used to create MPMV and
HIV vectors that are capable of transferring foreign genes
(Lever and Hunter, 2002). Mason-Pfizer monkey virus packaging signal is a
regulatory element located in the 5' UTR and is required for specific RNA
encapsidation (Mustafa et al., 2004, Harrison et al., 1995).                                                                  


gp70 SU - ENV polyprotein (coat polyprotein)- Marchler-Bauer A, Anderson JB, Derbyshire MK, DeWeese-Scott C, Gonzales NR, Gwadz M, Hao L, He S, Hurwitz DI, Jackson JD, Ke Z, Krylov D, Lanczycki CJ, Liebert CA, Liu C, Lu F, Lu S, Marchler GH, Mullokandov M, Song JS, Thanki N, Yamashita RA, Yin JJ, Zhang D, Bryant SH. (2007) CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res. 35: D237-40


Retroviral GAG p10 protein. This family consists of various retroviral GAG (core) polyproteins and encompasses the p10 region producing the p10 protein upon proteolytic cleavage of GAG by retroviral protease. The p10 or matrix protein (MA) is associated with the virus envelope glycoproteins in most mammalian retroviruses and may be involved in virus particle assembly, transport and budding. Some of the GAG polyproteins have alternate cleavage sites leading to the production of alternative and longer cleavage products (e.g. p19) the alignment of this family only covers the approximately N-terminal (GAG) 100 amino acid region of homology to p10. PMID: 9094640
Correct intracellular targeting of the gag to the nuclear compartment is a fundamental step in the retroviral life cycle. In an experiment by Bohl and coworkers(2005) the specific KKPKR motif of the gag protein was identified. The KKPKR is a region of basic residues within the NP24 domain. The NP24 domain is highly conserved among the phosphoproteins of various Betaretroviruses and play an important role in RNA packaging. Results of the experiment showed the KKPKR motif is required for virus replication. This finding was supported by experiments in which the KKPKR motif was deleted, and reduced viral RNA packaging 6-8 fold was observed. The deletion of this domain also affected the transient association of gag with nuclear pores (Bohl et al., 2005). Similarities in retroviral life cycle of the MPMV to diseases such as acquired immunodeficiency syndrome in humans enables MPMV to participate as a vital animal model to provides a way to test mechanisms and functions to improve human health.
                                                                    [http://nar.oxfordjournals.org/cgi/content/full/33/suppl_1/D121- Image: Rfam: annotating non-coding RNAs in complete genomes]


Virus infects during its life cycle a single type of vertebrate host. Viral hosts belong to the Domain Eucarya.
==References==


Domain Eucarya Kingdom Animalia.
Blaise, S., Mangeney, M., Heidmann, T. 2001.The envelope of Mason-Pfizer monkey 
virus has immunosuppressive properties. Journal of General Virology. 82:1597-1600.


Kingdom Animalia Phylum Chordata.
Bohl, C.R., Brown, S.M., Weldon Jr, R.A. 2005. The pp24 phosphoprotein of Mason-Pfizer monkey virus contributes to viral genome packaging. Retrovirology 2:68.


Phylum Vertebrata Subphylum Vertebrata.
Chappey,C. Direct Submission. Submitted (12-NOV-1997) NIH, NLM, Rockville Pike, Bethesda, MD 20894, USA.


Class Mammalia.
Chopra, C.H., Mason, M. M. 1970. A new virus in a spontaneous mammary tumor of a rhesus monkey. Cancer Research. 30:2081-2086.


Class Mammalia Order Primates.  
Conte, R.M., Klikova, M., Hunter, E., Matthews, S. 1997. The three-dimensional solution structure of the matrix protein from the type D retrovirus, the Mason-Pfizer monkey virus, and implications for the morphology of retroviral assembly. The European Molecular Biology Organization. 16(19):5819-5826.
http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/


Isolate abundance in healthy rhesus monkeys
De las Heras, M., Sharp, J.M., Garica de Jalon, J.A., Dewar, P. 1991. Enzootic nasal tumour of goats: demonstration of a type D-realted retrovirus in nasal fluids and tumours. Journal of General Virology. 72:2533-2535.


Symptoms
Fine, D.L., Landon, J.C., Pienta, R.J., Kubicek, M.T., Valerio, M.G., Loeb, W.F., & Chopra, H.C. 1975. Responses of infant rhesus monkeys to inoculation with Mason-Pfizer monkey virus materials. Journal of the National Cancer Institute. 54:651-658


With direct hybridization of radioactive MPMV
Fine, D., & Schochetman, G. 1978. Type D retroviruses: a review. Cancer Research 38:3123-3139.
70S RNA to DNA of various animal species, it has been
shown that a portion (approximately 20%) of the MPMV
genome was present in the cellular DNA of several Old
World monkeys of the subfamily Cercopithecinae (34). No
sequence homology was observed between MPMV and the
cellular DNA's of New World monkeys, apes (including
man), and several nonprimates (Fine and Schochetman, 1978).


RT-IN - RT_Rtv: Reverse transcriptases (RTs) from retroviruses (Rtvs). RTs catalyze the conversion of single-stranded RNA into double-stranded viral DNA for integration into host chromosomes. Proteins in this subfamily contain long terminal repeats (LTRs) and are multifunctional enzymes with RNA-directed DNA polymerase, DNA directed DNA polymerase, and ribonuclease hybrid (RNase H) activities. The viral RNA genome enters the cytoplasm as part of a nucleoprotein complex, and the process of reverse transcription generates in the cytoplasm forming a linear DNA duplex via an intricate series of steps. This duplex DNA is colinear with its RNA template, but contains terminal duplications known as LTRs that are not present in viral RNA. It has been proposed that two specialized template switches, known as strand-transfer reactions or "jumps", are required to generate the LTRs. PMID 9831551
Griffiths-Jones, S., Moxon, S., Marshal, M., Khannal, A., Eddy, S. R., Batemen, A. 2005. Nucleic Acids Research. 33:D121-D124


==Current Research==
Harrison, GP; Hunter E, Lever AM (1995). "Secondary structure model of the Mason-Pfizer monkey virus 5' leader sequence: identification of a structural motif common to a variety of retroviruses". J Virol 69: 2175–2186. PMID 7884866.
 
Huang, H., Chopra, R., Verdine, G.L., Harrison,  S.C. 1998. Structure of a covalently trapped catalytic complex of HIV reverse transcriptase: implications of drug resistance.  Science.  282(5394):1669-1675.
 
ICTVdB Management (2006). 00.061.1.01.003. Mason-Pfizer monkey virus. In: ICTVdB - The Universal Virus Database, version 4. Büchen-Osmond, C. (Ed), Columbia University, New York, USA.
 
Lever , A. M. L., Hunter, E. 2002. Defective packaging non-oncoviral vectors based on MPMV and HIV. US 6,294,165 B1:1-23.
 
Mustafa, F; Lew KA, Schmidt RD, Browning MT, Rizvi TA (2004). "Mutational analysis of the predicted secondary RNA structure of the Mason-Pfizer monkey virus packaging signal". Virus Res 99: 35–46. doi:10.1016/j.virusres.2003.09.012. PMID 14687944.


Enter summarries of the most rescent research here--at least three required
Parker, S.D., Hunter, E. 2001. Activation of the Mason-Pfizer monkey virus protease within immature capsids in vitro. Proceedings of the National Academy of Sciences of the United States of America. 98:14631-14636.


1) MPMV as a vector
Petropoulos,C.J.(1997). Appendix 2: Retroviral taxonomy, protein structure, sequences, and genetic maps (in) Coffin,J.M. (Ed.);RETROVIRUSES:757;Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, NY, USA.


2) Ancestral relations, origins
Sakalian, M., Dittmer, S., Gandy, D. A., Rapp, N. D., Zabransky, A., Hunter, E. 2002. The Mason-Pfizer monkey virus internal scaffold domain enables in vitro assembly of human immunodeficiency virus type 1 gag. Journal of Virology. 76:10811-10820


3)


==References==
[Sample reference] [http://ijs.sgmjournals.org/cgi/reprint/50/2/489 Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "''Palaeococcus ferrophilus'' gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". ''International Journal of Systematic and Evolutionary Microbiology''. 2000. Volume 50. p. 489-500.]


Edited by student of [mailto:elilly@umassd.edu Emily Lilly] at University of Massachusetts Dartmouth.
Edited by student of [mailto:elilly@umassd.edu Emily Lilly] at University of Massachusetts Dartmouth.

Latest revision as of 15:08, 20 August 2010

This student page has not been curated.

A Microbial Biorealm page on the genus Mason pfizer monkey virus

ICTV Classification

Higher order taxa

Viruses; Retro-transcribing viruses; Retroviridae; Orthoretrovirinae; Betaretrovirus (Chappy, C., 1997, Petropoulos, C.J., 1997).

Species

Genus species: Mason Pfizer Monkey Virus (Chappy, C., 1997, Petropoulos, C.J., 1997).

Description and significance

Mason Pfizer Monkey virus (MPMV) is a simian retrovirus (SRV), as well as the most thoroughly understood of the D-type Betaretrovirus. MPMV is the prototype for the D-type retroviruses. The fundamental assembly steps (gag particle formation, transport to the membrane, membrane interaction/viral budding, and viral release) are separate sequential processes allowing this virus to serve as an important model of retroviral assembly (Parker and Hunter, 2001). MPMV was first observed by Harish C. Chopra and Marcus M. Mason in 1970 from a spontaneous breast adenocarcinoma in an 8-year old rhesus monkey (Macaca mulatta) that had been in estrus for approximately one year (Chopra and Mason, 1970). MPMV has properties similar to the C-type and B-type viruses but is morphologically distinct (Fine and Schochetman, 1978), which initially designated the virus into the genus Oncornavirus D. However, after further characterization of the virus, the recent taxonomic genus classification has been changed to Betaretrovirus. MPMV is distinguished by accumulation of A-type intracellular particles in the cytoplasm and budding release to acquire viral protease activity. MPMV is pathogenic in Old World monkeys, Family Cercopithecidae (Fine and Schochetman, 1978) and causes immunodeficiency syndrome (Bohl et al., 2005) and tumors (De las Heras et al., 1991).

Initially the classification of the virus was based on the idea the virus induced simian AIDS (SAIDS), however, it is now known that SRVs are unrelated to simian immunodeficiency virus (SIV), which is currently recognized as the simian counterpart of the human immunodeficiency virus (Conte et al., 1997).

Genome structure

MPMV genome is dimeric, not segmented, and consists of a single molecule of linear, positive-sense, single-stranded RNA. The genome has been fully sequenced and the complete genome is of one monomer of 8,557 nucleotides in length. The genome has terminally redundant sequences that have long terminal repeats (LTR) of about 350 nucleotides. The 5'–end of the genome has a methylated nucleotide cap; cap sequence is of type 1 m7G5ppp5'GmpNp. The 3'–terminus of each monomer has a poly (A) tract, a tRNA–like structure, and accepts lysin. - ICTVdB - The Universal Virus Database, version 4.

The genome contains four protein coding genes, and two non protein coding genes. gag-pro-pol-env genes (MPMVgp1) code for protein products: Pr95, DU, RT-IN, gp70 SU, gp20 TM, and p12 PR. The gag gene (MPMVgp2) codes for protein products: Pr78, p14 NC, p10 MA, p24, p12, and p 27. Non-protein coding genes are pro, (MPMVgp3) and pol, (MPMVgp4) - (Chappy, C., 1997, Petropoulos, C.J., 1997).

Virion Structure

MPMV consists of an envelope, a nucleocapsid, and a nucleoid. Virus capsid (core) is enveloped. Proteins constitute about 60% of the particle weight. The viral genome encodes structural proteins and non-structural proteins, in which the non-structural proteins code for an RNA-dependent DNA polymerase. Lipids are present and located in the envelope, and the virus is composed of 35% lipids by weight. The composition of viral lipids and host cell membranes are similar. The lipids are of host origin and are derived from plasma membranes - ICTVdB - The Universal Virus Database, version 4..

Two types of particles classify MPMV. A-type particles are intracytoplasmic,electron-dense, ring-shaped particles measuring about 70 mµ in diameter. These immature particles pre-assemble in the cytoplasm and may occur singly or in cluster (Mason, 1970). Fully formed immature particles subsequently migrate to the plasma membrane where envelopment and budding occur at the cell surface (Sakalian et al., 2002). Upon release, nascent immature particles undergo a maturation process to acquire infectivity (Bohl et al., 2005). These mature extracellular particles are composed of a well defined spherical oval membrane and a central dense nucleoid measuring about 110 mµ in diameter. The mature particles are connected to or very close the plasma membrane (Chopra and Mason, 1970).


MPMV contains unique D-type morphology, similar yet distinguished morphology from type-C and type-B retrovirus. Less dense knob shaped surface spikes on the envelope, cylindrical capsids (Bohl et.al., 2005), size of intracytoplasmic A-type particles, and eccentric nucleoid region (Fine and Schochetman, 1978) distinguishes MPMV as a D-type Betaretrovirus.

Ecology

Mason Pfizer monkey virus was first isolated from mammary breast adenocarcinoma and infects a single type of vertebrate host during its life cycle. Viral hosts belong to the Domain Eucarya, Kingdom Animalia, Phylum Chordata, Subphylum Vertebrata, Class Mammalia, Order Primates - ICTVdB - The Universal Virus Database, version 4.

Exogenous and endogenous D-type viruses infect a variety of mammalian hosts including New World monkeys, (squirrel monkey retrovirus [SMRV]), sheep (Jaagsiekte sheep retroviruss), goat (enzootic nasal tumor virus), as well as D-type virus sequences isolated from humans (Bohl et al., 2005).

With direct hybridization of radioactive MPMV 70S RNA to DNA of various animal species, it has been shown that a portion(approximately 20%) of the MPMV genome was present in the cellular DNA of several Old World monkeys of the subfamily Cercopithecinae. No sequence homology was observed between MPMV and the cellular DNA's of New World monkeys, apes (including man), and several non-primates (Fine and Schochetman, 1978) indicating pathogenicity of MPMV occurs only in Old World monkeys.

Pathology

By itself, genomic nucleic acid of MPMV is not infectious. Viral protease activity is strictly limited to the completion of the viral budding process (Parker and Hunter, 2001).

Reverse transcriptases (RTs) catalyze the conversion of single-stranded RNA into double-stranded viral DNA for integration into host chromosomes. Proteins in this subfamily contain long terminal repeats (LTRs) and are multifunctional enzymes with RNA-directed DNA polymerase, DNA directed DNA polymerase, and ribonuclease hybrid (RNase H) activities. The viral RNA genome enters the cytoplasm as part of a nucleoprotein complex, and the process of reverse transcription generates in the cytoplasm forming a linear DNA duplex via an intricate series of steps. This duplex DNA is collinear with its RNA template, but contains terminal duplications known as LTRs that are not present in viral RNA. It has been proposed that two specialized template switches, known as strand-transfer reactions or "jumps", are required to generate the LTRs - (Huang et al., 1998).

Infection by retroviruses is associated with immune cell dysfunction. MPMV induces a fatal immunodeficiency syndrome in rhesus macaques (Conte et al., 1997). Newborn rhesus monkeys experimentally inoculated with MPMV developed a wasting disease within a few weeks accompanied by opportunistic infections including pneumonia, enteritis and rashes. Macaques naturally infected in primate centers and zoos die from opportunistic infections. While the virus was widespread, post-mortem examination revealed only lymphadenopathy and thymic atrophy. The opportunistic infections as a thymic target supports the virus exerts a T-cell immunosuppressive effect, as has been suggested for other D-type retroviruses (Fine et al., 1975.)

The MPMV envelope has been shown to have an immunosuppressive effect in vivo by using an assay involving rejection of tumor cells in immuno-competent mice. The experimental results also support an initiation of T-cell response with MPMV infection. The immunosuppressive properties of MPMV does not function based solely on a well conserved domain of 17 amino acids located within the transmembrane subunit of retroviral envelopes, but several domains within the envelope protein, and may be dependent on the overall structure of the protein (Blaise et al., 2001).

Current Research

MPMV is an important model to study human disease, and can be used experimentally as a tool to find potential inhibitors of HIV immature particle assembly. In an experiment by Sakalian and coworkers (2002), Assembly of HIV gag was enabled with regions of MPMV gag inserted into the HIV gag to create chimeric gag molecules. These chimeras were capable of assembly into immature capsid-like structures in vitro. Chimeric species containing large regions of MPMV gag fused to HIV gag failed to assemble. Species consisting of only the MPMV p12 region and its internal scaffold domain (ISD) fused to HIV gag were capable of assembly, however at reduced kinetics compared to the MPMV gag. The ISDs ability to induce assembly of the HIV gag in the plasma membrane, proposes a common requirement for a concentrating factor in retrovirus assembly. The function of the HIV gag domain remained essential, as confirmed by an assembly-defective mutant of HIV CA, M185A, that abolished assembly when introduced into the chimera. The continued requirement for HIV gag domain function in the assembly of chimeric molecules will allow in vitro systems to be used for analysis of potential inhibitors of HIV immature particle assembly (Sakalian et al., 2002).


Complete labeled image.JPG

MPMV is also an effective tool for gene therapy. Novel vectors are capable of producing MPMV proteins but not packaging MPMV RNA, and the information about the packaging signal in MPMV and HIV can be used to create MPMV and HIV vectors that are capable of transferring foreign genes (Lever and Hunter, 2002). Mason-Pfizer monkey virus packaging signal is a regulatory element located in the 5' UTR and is required for specific RNA encapsidation (Mustafa et al., 2004, Harrison et al., 1995).


Correct intracellular targeting of the gag to the nuclear compartment is a fundamental step in the retroviral life cycle. In an experiment by Bohl and coworkers(2005) the specific KKPKR motif of the gag protein was identified. The KKPKR is a region of basic residues within the NP24 domain. The NP24 domain is highly conserved among the phosphoproteins of various Betaretroviruses and play an important role in RNA packaging. Results of the experiment showed the KKPKR motif is required for virus replication. This finding was supported by experiments in which the KKPKR motif was deleted, and reduced viral RNA packaging 6-8 fold was observed. The deletion of this domain also affected the transient association of gag with nuclear pores (Bohl et al., 2005). Similarities in retroviral life cycle of the MPMV to diseases such as acquired immunodeficiency syndrome in humans enables MPMV to participate as a vital animal model to provides a way to test mechanisms and functions to improve human health.

                                                                   Image: Rfam: annotating non-coding RNAs in complete genomes

References

Blaise, S., Mangeney, M., Heidmann, T. 2001.The envelope of Mason-Pfizer monkey virus has immunosuppressive properties. Journal of General Virology. 82:1597-1600.

Bohl, C.R., Brown, S.M., Weldon Jr, R.A. 2005. The pp24 phosphoprotein of Mason-Pfizer monkey virus contributes to viral genome packaging. Retrovirology 2:68.

Chappey,C. Direct Submission. Submitted (12-NOV-1997) NIH, NLM, Rockville Pike, Bethesda, MD 20894, USA.

Chopra, C.H., Mason, M. M. 1970. A new virus in a spontaneous mammary tumor of a rhesus monkey. Cancer Research. 30:2081-2086.

Conte, R.M., Klikova, M., Hunter, E., Matthews, S. 1997. The three-dimensional solution structure of the matrix protein from the type D retrovirus, the Mason-Pfizer monkey virus, and implications for the morphology of retroviral assembly. The European Molecular Biology Organization. 16(19):5819-5826.

De las Heras, M., Sharp, J.M., Garica de Jalon, J.A., Dewar, P. 1991. Enzootic nasal tumour of goats: demonstration of a type D-realted retrovirus in nasal fluids and tumours. Journal of General Virology. 72:2533-2535.

Fine, D.L., Landon, J.C., Pienta, R.J., Kubicek, M.T., Valerio, M.G., Loeb, W.F., & Chopra, H.C. 1975. Responses of infant rhesus monkeys to inoculation with Mason-Pfizer monkey virus materials. Journal of the National Cancer Institute. 54:651-658

Fine, D., & Schochetman, G. 1978. Type D retroviruses: a review. Cancer Research 38:3123-3139.

Griffiths-Jones, S., Moxon, S., Marshal, M., Khannal, A., Eddy, S. R., Batemen, A. 2005. Nucleic Acids Research. 33:D121-D124

Harrison, GP; Hunter E, Lever AM (1995). "Secondary structure model of the Mason-Pfizer monkey virus 5' leader sequence: identification of a structural motif common to a variety of retroviruses". J Virol 69: 2175–2186. PMID 7884866.

Huang, H., Chopra, R., Verdine, G.L., Harrison, S.C. 1998. Structure of a covalently trapped catalytic complex of HIV reverse transcriptase: implications of drug resistance. Science. 282(5394):1669-1675.

ICTVdB Management (2006). 00.061.1.01.003. Mason-Pfizer monkey virus. In: ICTVdB - The Universal Virus Database, version 4. Büchen-Osmond, C. (Ed), Columbia University, New York, USA.

Lever , A. M. L., Hunter, E. 2002. Defective packaging non-oncoviral vectors based on MPMV and HIV. US 6,294,165 B1:1-23.

Mustafa, F; Lew KA, Schmidt RD, Browning MT, Rizvi TA (2004). "Mutational analysis of the predicted secondary RNA structure of the Mason-Pfizer monkey virus packaging signal". Virus Res 99: 35–46. doi:10.1016/j.virusres.2003.09.012. PMID 14687944.

Parker, S.D., Hunter, E. 2001. Activation of the Mason-Pfizer monkey virus protease within immature capsids in vitro. Proceedings of the National Academy of Sciences of the United States of America. 98:14631-14636.

Petropoulos,C.J.(1997). Appendix 2: Retroviral taxonomy, protein structure, sequences, and genetic maps (in) Coffin,J.M. (Ed.);RETROVIRUSES:757;Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, NY, USA.

Sakalian, M., Dittmer, S., Gandy, D. A., Rapp, N. D., Zabransky, A., Hunter, E. 2002. The Mason-Pfizer monkey virus internal scaffold domain enables in vitro assembly of human immunodeficiency virus type 1 gag. Journal of Virology. 76:10811-10820


Edited by student of Emily Lilly at University of Massachusetts Dartmouth.