Mason pfizer monkey virus: Difference between revisions

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MPMV consist 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.]
MPMV consist 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.]


Two types of particles classify 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 (Chopra and Mason, 1970).
Two types of particles classify MPMV.  A-type particles are intracytoplasmic,electron-dense, ring-shaped particles measuring about 70 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 in diameter. The mature particles are connected to or very close the plasma membrane (Chopra and Mason, 1970).





Revision as of 13:57, 18 December 2008

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) and is 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 is 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 SRV's are unrelated to simian immunodeficiency virus (SIV's), 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 consist 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 Betaretrovirus.

Ecology

Mason Pfizer monkey virus was first isolated from mammary breast adenocarcinoma in rhesus monkey, an Old World monkey, an 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 in 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 nonprimates (Fine and Schochetman, 1978) indicating virulence of MPMV occurs only in Cercopithecidae.

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, as well as 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 suggests 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 be immunosuppressive in vivo using an assay involving rejection of tumor cells in immuno-competent mice also supporting an initiation of T-cell response. 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, possibly dependent on the overall structure of the protein (Blaise et al., 2001).

Current Research

MPMV is an important model to study human disease, and MPMV can be used experimentally as a tool to find potential inhibitor of HIV immature particle assembly. In and 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 are 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, while species consisting of only the MPMV p12 region and its interal scaffold doman (ISD) fused to HIV gag were capable of assembly, however at reduced kinetics compared to the MPMV gag. The ISD's 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 inhibitor of HIV immature partical assembly (Sakalian et al., 2002).

MPMV is also an effective tool for gene thearapy. 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 et al., 2002).

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 and affected the transien 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 supports MPMV as a vital animal, and provide a way to test mechanisms and functions to improve human health.

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.

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. 2001. Defective packaging non-oncoviral vectors based on MPMV and HIV. US 6,294,165 B1:1-23.

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. 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.