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{{Curated}}
{{Viral Biorealm Family}}
[[Image:17_lores.jpg(felineleukemia).jpg|thumb|300px|right|Electron micrograph image of Feline Leukemia Virus, a virus in the Retroviridae family. From the [http://www.cdc.gov CDC].]]
==Baltimore Classification==
==Baltimore Classification==


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


Viruses; Retro-transcribing viruses; Reoviridae
Viruses; Retro-transcribing viruses; Retroviridae


===Genera===
===Genera===


Alpharetrovirus, Betaretrovirus, Spumavirus (examples)
* Orthoretrovirinae (subfamily)
** ''Alpharetrovirus''
** ''Betaretrovirus''
** ''Deltaretrovirus''
** ''Epsilonretrovirus''
** ''Gammaretrovirus''
** ''Lentivirus''
* Spumaretrovirinae (subfamily)
** ''Spumaretrovirus''
* [http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Tree&id=35276&lvl=3&lin=f&keep=1&srchmode=1&unlock Unclassified Retroviridae]


==Description and Significance==
==Description and Significance==


 
Retroviruses are viruses that are remarkable for their use of reverse transcription of viral RNA into DNA during replication.  Members of this family include [[Human immunodeficiency virus]] (the virus that causes AIDS), feline leukemia, and several cancer-causing viruses.  Retroviruses were discovered in 1908 by Vilhelm Ellermann and Oluf Bang.  The first sixty years of study of retroviruses focused exclusively on animal infection and disease.  In the 1960s and 1970s, study focused on the viral replication cycle and pathogenic effects at the cellular level.  Current study of retroviruses focuses on the diverse pathogenic effects of these viruses at the cellular and molecular levels.  Retroviruses were the first viruses to be modified for gene therapy, and continue to be used in the majority of gene therapy clinical trials.  (sources: [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=rv.TOC Coffin et al.], [http://pharmrev.aspetjournals.org/cgi/reprint/52/4/493 Hu and Pathak])


==Genome Structure==
==Genome Structure==


The genome of retroviridae is dimeric, unsegmented and contains a single molecule of linear. The genome is -RT and a positive-sense, single-stranded RNA. Minor species of non-genomic nucleic acid are also found in virions. The encapsidated nucleic acid is mainly of genomic origin but virions may also contain nucleic acid of host origin, including host RNA and fragments of host DNA believed to be incidental inclusions. The complete genome of one monomer is 700-11000 nucleotides long. The 5'-end of the genome has a methylated nucleotide cap with a cap sequence type 1 m7G5ppp5'GmpNp. The 3'-terminus of each monomer has a poly (A) tract and the terminus has a tRNA-like structure. (source: [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/index.htm ICTVdB Descriptions])
The genome of retroviridae is dimeric, unsegmented and contains a single molecule of linear. The genome is -RT and a positive-sense, single-stranded RNA. Minor species of non-genomic nucleic acid are also found in virions. The encapsidated nucleic acid is mainly of genomic origin but virions may also contain nucleic acid of host origin, including host RNA and fragments of host DNA believed to be incidental inclusions. The complete genome of one monomer is 7000-11000 nucleotides long. The 5'-end of the genome has a methylated nucleotide cap with a cap sequence type 1 m7G5ppp5'GmpNp. The 3'-terminus of each monomer has a poly (A) tract and the terminus has a tRNA-like structure. (source: [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.061.htm ICTVdB])


==Virion Structure of a Retroviridae==
==Virion Structure of a Retroviridae==


The virions of a retroviridae consist of an encelope, a nucleocapsid and a nucleoid. The virus capsid is enveloped. The virions are spherical to pleomorphic and measure 80-100 nm in diameter. The surface projections are small or distinctive glycoprotein spikes that cover the surface evenly. The projections are densely dispersed and 8 nm long. The nucleoid is concentric or eccentric while the core is spherical. (source: [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/index.htm ICTVdB Descriptions])
The virions of a retroviridae consist of an envelope, a nucleocapsid and a nucleoid. The virus capsid is enveloped. The virions are spherical to pleomorphic and measure 80-100 nm in diameter. The surface projections are small or distinctive glycoprotein spikes that cover the surface evenly. The projections are densely dispersed and 8 nm long. The nucleoid is concentric or eccentric while the core is spherical. (source: [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.061.htm ICTVdB])


==Reproduction Cycle of a Retroviridae in a Host Cell==
==Reproduction Cycle of a Retroviridae in a Host Cell==


The SU envelope glycoprotein binds to a specific receptor on the surface of the host targer cell to initiate the infection. The specificity of this interaction does much to determine the cell-tropism and pathogenesis of different retroviruses and even different isolates of the same virus. Murine reroviruses (MLVs) are sub-divided to three categories on the basis of receptor-determined host species specificity: ecotropic, xenotropic, and amphotropic. Ecotropic MLVs infect only mouse cells, xenotropic MLVs infect only non-mouse cells like rat and hamster, and amphotropic MLVs infect both mouse and non-mouse cells.  
Retrovirus virions enter host cells through interaction between a virally-encoded envelope protein and a cellular receptor.  Viral RNA is transcribed into a DNA copy by the enzyme reverse transcriptase which is present in the virion.  The viral DNA copy is integrated into, and becomes a permanent part of, the host genome.  This integrated DNA is referred to as a provirus.  The host cell's transcriptional and translational machinery expresses the viral genes. The host RNA polymerase II transcribes the provirus to create new viral RNA, which is then transported out of the nucleus by other cellular processes. A fraction of these new RNAs are spliced to allow expression of some genes, while others are left as full-length RNAs.  Viral proteins are synthesized by the host cell's translational machinery. Virions are assembled and bud from the host cell.


Interference between an exogenous virus and an endogenous virus of the same receptor specificity results in interference groups of viruses, as exemplified by ALVs. A number of retrovirus receptor molecules have been identified in recent years.
This reproduction cycle applies to all of the members of Retroviridae except for spumaviruses.  Spumaviruses complete reverse transcription in the virus-producing cells rather than infected target cells, and the infectious virus contains a DNA genome. (source:  [http://pharmrev.aspetjournals.org/cgi/reprint/52/4/493 Hu and Pathak])


There is a possibility that receptor binding results in conformational changes in the glycoprotein spike, revealing the fusion domain in the TM protein and resulting in the fusion of the virus envelope with the cell membrane. Very little is known about penetration and uncoating but it is known that uncoating is only partial. resulting eventually in a core particle within the cytoplasm. Reverse transcription occurs inside the ordered structure of this core particle. Reverse transcription is initiated but cannot be completed with the reactants free in solution, and aborts soon after.
==Viral Ecology & Pathology==


The d/s DNA product formed is known as provirus and differs from the vRNA in being longer by one U3,R,U5 sequence. There is a direct repear of this sequence present at each end of the provirus genome as a result, and these are known as the long terminal repeats (LTRs)Three forms of provirus DNA are found in all infected cells.
Retroviruses cause a wide variety of malignancies, immunodeficiencies, and neurological disorders affecting a wide variety of species.  According to [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=rv.TOC Coffin et al.], "Some of these disorders have significant agricultural impact, crippling farm animals during their most productive years, whereas others have a devastating medical and economic impact on humans. Still others, particularly many of the retrovirus-induced malignancies of rodents, were found originally in laboratory settings and provide excellent model systems for probing the biological and molecular mechanisms of carcinogenesis."  (source: [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=rv.TOC Coffin et al.])


Integration is a highly specific reaction with respect to the provirus, but random with respect to the host cell DNA. It is believed that the linear form, probably the direct product of reverse transcription, is the substrate used.
==Vaccines==
The failure of 'classical' vaccines to induce protection to the most important of all retroviruses, HIV, has led to the development of a huge variety of 'molecular vaccines', i.e. vaccines produced using modern molecular biological techniques. Such vaccines range from simple plasmid DNA coding for the genes of choice, through recombinant viruses carrying such genes to engineered bacteria designed to deliver HIV genes to the mucosal immune system. Evaluation of such vaccines in animal models has resulted in sporadic successes and many failures and the few human clinical trials have been, at best, negative. However, the relative success of molecular vaccines in combating other retroviral infections and the continuing refinement of HIV/SIV vaccines showing some efficacy suggests that a molecular AIDS vaccine may be achievable. (source: [http://www.horizonpress.com/retrovirus Kurth and Bannert])


The ends of the LTRs consist of inverted repeats of 4-6 bp. These are brought together to form a cleavage site for IN and are cleaved to form a staggered cut. This molecule is then inserted into the host cell DNA. The final results of the integration process is that the integrated provirus contains 1 or 2 less bases at the end of each LTR, the ends of the integrated LTRs always have the same sequence 5' - TG...CA - 3', and 4-6 bp of host cell DNA flanking the integrated provirus are duplicated.
==References==
 
These observations can be explained by a model where a staggered cut (5' overhang) is introduced into both the ends of the LTRs and the host cell DNA, followed by joining of the cut ends and repair of the free 3' ends. The provirus is present for the lifetime of the cell once it is integrated. There is no specific mechanism for the excision of the provirus and the infected cell cannot be cured.
 
The celllular transcriptional machinery is used by retroviruses for expression, although a few encode additional transcriptional and post-transcriptional regulatory factors - HTLV and HIV. They are therefore expressed like cellular genes. They make use of a number to 'tricks', such as splicing and ribosomal frameshifting to compress maximal information into a small genome.
 
Various LTRs have been intensively studied and dissected by molecular techniques in recent years. Some of these studies have been related to nucleotide sequencing and comparison with cellular promoter elements with known functions, nuclease protection studies, S1 protection to determine precise transcription start sites - DNAse I protection to determine DNA-binding protein sites in vitro transcription studies.
 
Splicing is regulated by the cellular apparatus which interacts with cis-acting sequences present in the mRNA. The proteins encoded by gag, pol and pro genes are expressed from a full length genomic RNA, vRNA. TIn complex retros like HTLV and Lentiviruses, multiply spliced mRNAs are produced. The patern of splicing in HIV is very complex.
 
Pro overlaps gag and/or pol, but is still expressed from the same full-length mRNA. Different viruses have a variety of post-transcriptional stratergies to do this. (source: [http://www-micro.msb.le.ac.uk/3035/Retroviruses.html Microbiology@Leicester])


==Viral Ecology & Pathology==
[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=rv.TOC Coffin et al.  <u>Retroviruses</u>.  Cold Spring Harbor Laboratory Press, 1997.]


The pathogenesis of retrovirus has been concentrated on oncogenesis and more recently AIDS but retroviruses cause a variety of haematopoetic and neurological conditions. Some such conditions caused by retroviridae are paralysis, wasting, ataxia, arthritis, dementia and neuropathy.
[http://pharmrev.aspetjournals.org/cgi/reprint/52/4/493 Hu, Wei-Shau and Vinay K. Pathak.  "Design of Retroviral Vectors and Helper Cells for Gene Therapy."  ''Pharmacological Reviews'' 52.4 (2000): 493-511.]
 
It was recently reported that an ancient retrotransposon insertion is the cause of Fukayama-type muscular dystrophy, one of the commonest autosomal recessive disorders in Japan. This is the only known instance of insertional mutagenesis of the human genome cause by this type of element to date, but it seems certain that other examples will be discovered in the future. (source: [http://www-micro.msb.le.ac.uk/3035/Retroviruses.html Microbiology@Leicester])
 
==References==


[http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/index.htm ICTVdB Descriptions]
[http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.061.htm ICTVdB - The Universal Virus Database, version 4. http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/]


[http://www-micro.msb.le.ac.uk/3035/Retroviruses.html Microbiology@Leicester]
[http://www.horizonpress.com/retrovirus Kurth, R; Bannert, N (2010) Retroviruses: Molecular Biology, Genomics and Pathogenesis. Caister Academic Press 978-1-904455-55-4]

Latest revision as of 00:33, 8 August 2010

This is a curated page. Report corrections to Microbewiki.

A Viral Biorealm page on the family Retroviridae

Electron micrograph image of Feline Leukemia Virus, a virus in the Retroviridae family. From the CDC.

Baltimore Classification

Higher order taxa

Viruses; Retro-transcribing viruses; Retroviridae

Genera

  • Orthoretrovirinae (subfamily)
    • Alpharetrovirus
    • Betaretrovirus
    • Deltaretrovirus
    • Epsilonretrovirus
    • Gammaretrovirus
    • Lentivirus
  • Spumaretrovirinae (subfamily)
    • Spumaretrovirus
  • Unclassified Retroviridae

Description and Significance

Retroviruses are viruses that are remarkable for their use of reverse transcription of viral RNA into DNA during replication. Members of this family include Human immunodeficiency virus (the virus that causes AIDS), feline leukemia, and several cancer-causing viruses. Retroviruses were discovered in 1908 by Vilhelm Ellermann and Oluf Bang. The first sixty years of study of retroviruses focused exclusively on animal infection and disease. In the 1960s and 1970s, study focused on the viral replication cycle and pathogenic effects at the cellular level. Current study of retroviruses focuses on the diverse pathogenic effects of these viruses at the cellular and molecular levels. Retroviruses were the first viruses to be modified for gene therapy, and continue to be used in the majority of gene therapy clinical trials. (sources: Coffin et al., Hu and Pathak)

Genome Structure

The genome of retroviridae is dimeric, unsegmented and contains a single molecule of linear. The genome is -RT and a positive-sense, single-stranded RNA. Minor species of non-genomic nucleic acid are also found in virions. The encapsidated nucleic acid is mainly of genomic origin but virions may also contain nucleic acid of host origin, including host RNA and fragments of host DNA believed to be incidental inclusions. The complete genome of one monomer is 7000-11000 nucleotides long. The 5'-end of the genome has a methylated nucleotide cap with a cap sequence type 1 m7G5ppp5'GmpNp. The 3'-terminus of each monomer has a poly (A) tract and the terminus has a tRNA-like structure. (source: ICTVdB)

Virion Structure of a Retroviridae

The virions of a retroviridae consist of an envelope, a nucleocapsid and a nucleoid. The virus capsid is enveloped. The virions are spherical to pleomorphic and measure 80-100 nm in diameter. The surface projections are small or distinctive glycoprotein spikes that cover the surface evenly. The projections are densely dispersed and 8 nm long. The nucleoid is concentric or eccentric while the core is spherical. (source: ICTVdB)

Reproduction Cycle of a Retroviridae in a Host Cell

Retrovirus virions enter host cells through interaction between a virally-encoded envelope protein and a cellular receptor. Viral RNA is transcribed into a DNA copy by the enzyme reverse transcriptase which is present in the virion. The viral DNA copy is integrated into, and becomes a permanent part of, the host genome. This integrated DNA is referred to as a provirus. The host cell's transcriptional and translational machinery expresses the viral genes. The host RNA polymerase II transcribes the provirus to create new viral RNA, which is then transported out of the nucleus by other cellular processes. A fraction of these new RNAs are spliced to allow expression of some genes, while others are left as full-length RNAs. Viral proteins are synthesized by the host cell's translational machinery. Virions are assembled and bud from the host cell.

This reproduction cycle applies to all of the members of Retroviridae except for spumaviruses. Spumaviruses complete reverse transcription in the virus-producing cells rather than infected target cells, and the infectious virus contains a DNA genome. (source: Hu and Pathak)

Viral Ecology & Pathology

Retroviruses cause a wide variety of malignancies, immunodeficiencies, and neurological disorders affecting a wide variety of species. According to Coffin et al., "Some of these disorders have significant agricultural impact, crippling farm animals during their most productive years, whereas others have a devastating medical and economic impact on humans. Still others, particularly many of the retrovirus-induced malignancies of rodents, were found originally in laboratory settings and provide excellent model systems for probing the biological and molecular mechanisms of carcinogenesis." (source: Coffin et al.)

Vaccines

The failure of 'classical' vaccines to induce protection to the most important of all retroviruses, HIV, has led to the development of a huge variety of 'molecular vaccines', i.e. vaccines produced using modern molecular biological techniques. Such vaccines range from simple plasmid DNA coding for the genes of choice, through recombinant viruses carrying such genes to engineered bacteria designed to deliver HIV genes to the mucosal immune system. Evaluation of such vaccines in animal models has resulted in sporadic successes and many failures and the few human clinical trials have been, at best, negative. However, the relative success of molecular vaccines in combating other retroviral infections and the continuing refinement of HIV/SIV vaccines showing some efficacy suggests that a molecular AIDS vaccine may be achievable. (source: Kurth and Bannert)

References

Coffin et al. Retroviruses. Cold Spring Harbor Laboratory Press, 1997.

Hu, Wei-Shau and Vinay K. Pathak. "Design of Retroviral Vectors and Helper Cells for Gene Therapy." Pharmacological Reviews 52.4 (2000): 493-511.

ICTVdB - The Universal Virus Database, version 4. http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/

Kurth, R; Bannert, N (2010) Retroviruses: Molecular Biology, Genomics and Pathogenesis. Caister Academic Press 978-1-904455-55-4