A retrovirus is a type of
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
that inserts a DNA copy of its
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
genome into the
DNA of a
host cell
In biology and medicine, a host is a larger organism that harbours a smaller organism; whether a parasitic, a mutualistic, or a commensalist ''guest'' (symbiont). The guest is typically provided with nourishment and shelter. Examples include a ...
that it invades, thus changing the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
of that cell. Once inside the host cell's
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, the virus uses its own
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus ''retro'' (backwards). The new DNA is then
incorporated into the host cell genome by an
integrase
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...
enzyme, at which point the retroviral DNA is referred to as a
provirus A provirus is a virus genome that is integrated into the DNA of a host cell. In the case of bacterial viruses (bacteriophages), proviruses are often referred to as prophages. However, proviruses are distinctly different from prophages and these ter ...
. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus.
Although retroviruses have different subfamilies, they have three basic groups: the
oncoretroviruses (oncogenic retroviruses), the
lentivirus
''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
es (slow retroviruses) and the
spumavirus
''Spumaretrovirinae'', commonly called spumaviruses (, Latin for "foam") or foamyviruses, is a subfamily of the ''Retroviridae'' family. ICTVMaster Species List 2018a v1MSL including all taxa updates since the 2017 release. Fall 2018 (MSL #33) Sp ...
es (foamy viruses).
The oncoretroviruses are able to cause cancer in some species, the lentiviruses are able to cause severe immunodeficiency and death in humans and other animals, and the spumaviruses are benign and not linked to any disease in humans or animals.
Many retroviruses cause serious diseases in humans, other mammals, and birds.
Human retroviruses include
HIV-1
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey, ...
and
HIV-2
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey, ...
, the cause of the disease
AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...
. Also,
human T-lymphotropic virus
The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and ...
(HTLV) causes disease in humans. The murine leukemia viruses (MLVs) cause cancer in mouse hosts. Retroviruses are valuable research tools in molecular biology, and they have been used successfully in gene delivery systems.
Evidence from
endogenous retrovirus
Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome (l ...
es suggests that retroviruses have been infecting vertebrates for at least 450 million years.
Structure
Virion
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
s, viruses in the form of independent particles of retroviruses, consist of enveloped particles about 100
nm in diameter. The outer lipid envelope consists of glycoprotein. The virions also contain two identical single-stranded
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
molecules 7–10
kilobases in length. The two molecules are present as a dimer, formed by base pairing between complementary sequences. Interaction sites between the two RNA molecules have been identified as a "
kissing stem-loop
In genetics, a kissing stem-loop, or kissing stem loop interaction, is formed in ribonucleic acid (RNA) when two bases between two hairpin loops pair. These intra- and intermolecular kissing interactions are important in forming the tertiary or q ...
".
Although virions of different retroviruses do not have the same
morphology
Morphology, from the Greek and meaning "study of shape", may refer to:
Disciplines
*Morphology (archaeology), study of the shapes or forms of artifacts
*Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...
or biology, all the virion components are very similar.
The main virion components are:
*
Envelope
An envelope is a common packaging item, usually made of thin, flat material. It is designed to contain a flat object, such as a letter or card.
Traditional envelopes are made from sheets of paper cut to one of three shapes: a rhombus, a shor ...
: composed of lipids (obtained from the host
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
during the
budding
Budding or blastogenesis is a type of asexual reproduction in which a new organism develops from an outgrowth or bud due to cell division at one particular site. For example, the small bulb-like projection coming out from the yeast cell is know ...
process) as well as glycoprotein encoded by the
env gene. The retroviral envelope serves three distinct functions: protection from the extracellular environment via the
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
, enabling the retrovirus to enter/exit host cells through
endosomal
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
membrane trafficking Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory c ...
, and the ability to directly enter cells by fusing with their membranes.
*
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
: consists of a
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ( ...
RNA. It has a cap at the
5' end and a poly(A) tail at the 3' end. Genomic RNA (gRNA) is produced as a result of host RNA polymerase II (Pol II) activity and by adding a 5' methyl cap and a 3' poly-A tail is processed as a host mRNA.
The RNA genome also has terminal noncoding regions, which are important in replication, and internal regions that encode virion proteins for
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
. The 5' end includes four regions, which are R, U5, PBS, and L. The R region is a short repeated sequence at each end of the genome used during the
reverse transcription
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
to ensure correct end-to-end transfer in the growing chain. U5, on the other hand, is a short unique sequence between R and PBS. PBS (primer binding site) consists of 18 bases complementary to 3' end of tRNA primer. L region is an untranslated leader region that gives the signal for packaging of the genome RNA. The 3' end includes three regions, which are PPT (polypurine tract), U3, and R. The PPT is a primer for plus-strand DNA synthesis during
reverse transcription
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
. U3 is a sequence between PPT and R, which serves as a signal that the provirus can use in
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
. R is the terminal repeated sequence at 3' end.
*
Protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s: consisting of gag proteins,
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
(PR), pol proteins, and env proteins.
**
Group-specific antigen
Group-specific antigen, or gag, is the polyprotein that contains the core structural proteins of an Ortervirus (except ''Caulimoviridae''). It was named as such because scientists used to believe it was antigenic. Now it is known that it makes up ...
(gag) proteins are major components of the viral
capsid
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may ...
, which are about 2000–4000 copies per virion. Gag possesses two nucleic acid binding domains, including matrix (MA) and nucleocapsid (NC). Specifically recognizing, binding, and packaging the retroviral genomic RNA into assembling virions is one of the important functions of Gag protein. Gag interactions with cellular RNAs also regulate aspects of assembly. The expression of ''gag'' alone gives rise to assembly of immature virus-like particles that bud from the plasma membrane. In all retroviruses the Gag protein is the precursor to the internal structural protein.
**
Protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
(pro) is expressed differently in different viruses. It functions in proteolytic cleavages during virion maturation to make mature gag and pol proteins. Retroviral Gag proteins are responsible for coordinating many aspects of virion assembly.
**
Pol proteins are responsible for synthesis of viral DNA and integration into host DNA after infection.
**
Env proteins
env is a shell command for Unix and Unix-like operating systems. It is used to either print a list of environment variables or run another utility in an altered environment without having to modify the currently existing environment. Using env, ...
play a role in association and entry of virions into the host cell.
Possessing a functional copy of an
env gene is what makes retroviruses distinct from
retroelements
Retrotransposons (also called Class I transposable elements or transposons via RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through ...
. The ability of the retrovirus to bind to its target host cell using specific cell-surface receptors is given by the surface component (SU) of the Env protein, while the ability of the retrovirus to enter the cell via
membrane fusion
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...
is imparted by the membrane-anchored trans-membrane component (TM). Thus it is the Env protein that enables the retrovirus to be infectious.
** Several protein species are associated with the RNA in the retrovirus virion. Nucleocapsid (NC) protein is the most abundant protein, which coats the RNA; while other proteins, present in much smaller amounts and have enzyme activities. Some enzyme activities that are present in the retrovirus virion includes RNA-dependent DNA polymerase (reverse transcriptase; RT), DNA-dependent DNA polymerase, Ribonuclease H (RNase H) Integrase and Protease.
The retroviral RNases H encoded by all retroviruses, including HIV have been demonstrated to show three different modes of cleavage: internal, DNA 3′ end-directed, and RNA 5′ end-directed. All three modes of cleavage constitute roles in reverse transcription. Therefore, The RNase H activity is essential in several aspects of reverse transcription. The use of an RNase H activity during retroviral replication displays a unique strategy to copy a single-stranded RNA genome into a double-stranded DNA, since the minus-strand DNA are complementary and make base pairing to retrovirus genome in the first cycle of DNA synthesis. The RNase H ribonuclease activity is also required in the retroviral life cycle, since it generates and removes primers essential by the Reverse Transcriptase (RT) for the initiation of DNA synthesis. Retroviruses that are lacking RNase H activity are noninfectious.
Genomic structure
The retroviral genome is packaged as viral particles. These viral particles are dimers of single-stranded, positive-sense, linear RNA molecules.
Retroviruses (and
orterviruses in general) follow a layout of 5'–''gag''–''pro''–''pol''–''env''–3' in the RNA genome. ''gag'' and ''pol'' encode polyproteins, each managing the capsid and replication. The ''pol'' region encodes enzymes necessary for viral replication, such as reverse transcriptase, protease and integrase. Depending on the virus, the genes may overlap or fuse into larger polyprotein chains. Some viruses contain additional genes. The lentivirus genus, the spumavirus genus, the HTLV / bovine leukemia virus (BLV) genus, and a newly introduced fish virus genus are retroviruses classified as complex. These viruses have genes called accessory genes, in addition to gag, pro, pol and env genes. Accessory genes are located between pol and env, downstream from the env, including the U3 region of LTR, or in the env and overlapping portions. While accessory genes have auxiliary roles, they also coordinate and regulate viral gene expression.
In addition, some retroviruses may carry genes called oncogenes or onc genes from another class. Retroviruses with these genes (also called transforming viruses) are known for their ability to quickly cause tumors in animals and transform cells in culture into an oncogenic state.
The polyproteins are cleaved into smaller proteins each with their own function. The nucleotides encoding them are known as ''subgenes''.
Multiplication
![Life Cycle of a Retrovirus](https://upload.wikimedia.org/wikipedia/commons/2/2b/Life_Cycle_of_a_Retrovirus.svg)
When retroviruses have integrated their own genome into the
germ line
In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They ...
, their genome is
passed on to a following generation. These
endogenous retrovirus
Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome (l ...
es (ERVs), contrasted with
exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogeno ...
ones, now make up 5–8% of the human genome. Most insertions have no known function and are often referred to as "
junk DNA
Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not genetic code, encode protein sequences. Some non-coding DNA is Transcription (genetics), transcribed into functional non-coding RNA molecules (e.g. transfer RNA, micro ...
". However, many endogenous retroviruses play important roles in host biology, such as control of gene transcription, cell fusion during
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
l development in the course of the
germination
Germination is the process by which an organism grows from a seed or spore. The term is applied to the sprouting of a seedling from a seed of an angiosperm or gymnosperm, the growth of a sporeling from a spore, such as the spores of fungi, fer ...
of an
embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
, and resistance to exogenous retroviral infection. Endogenous retroviruses have also received special attention in the research of
immunology
Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
-related pathologies, such as
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s like
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, although endogenous retroviruses have not yet been proven to play any causal role in this class of disease.
While transcription was classically thought to occur only from DNA to RNA,
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
transcribes RNA into DNA. The term "retro" in retrovirus refers to this reversal (making DNA from RNA) of the usual direction of transcription. It still obeys the
central dogma of molecular biology
The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system. It is often stated as "DNA makes RNA, and RNA makes protein", although this is not its original meaning. It was first stated by ...
, which states that information can be transferred from nucleic acid to nucleic acid but cannot be transferred back from protein to either protein or nucleic acid. Reverse transcriptase activity outside of retroviruses has been found in almost all
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s, enabling the generation and insertion of new copies of
retrotransposon
Retrotransposons (also called Class I transposable elements or transposons via RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through ...
s into the host genome. These inserts are transcribed by enzymes of the host into new RNA molecules that enter the cytosol. Next, some of these RNA molecules are translated into viral proteins. The proteins encoded by the gag and pol genes are translated from genome-length mRNAs into Gag and Gag–Pol polyproteins. In example, for the ''gag'' gene; it is translated into molecules of the capsid protein, and for the ''pol'' gene; it is translated into molecules of reverse transcriptase. Retroviruses need a lot more of the Gag proteins than the Pol proteins and have developed advanced systems to synthesize the required amount of each. As an example, after Gag synthesis nearly 95 percent of the ribosomes terminate translation, while other ribosomes continue translation to synthesize Gag–Pol. In the rough endoplasmic reticulum glycosylation begins and the ''env'' gene is translated from spliced mRNAs in the rough endoplasmic reticulum, into molecules of the envelope protein. When the envelope protein molecules are carried to the Golgi complex, they are divided into surface glycoprotein and transmembrane glycoprotein by a host protease. These two glycoprotein products stay in close affiliation, and they are transported to the plasma membrane after further glycosylation.
It is important to note that a retrovirus must "bring" its own reverse transcriptase in its
capsid
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may ...
, otherwise it is unable to utilize the enzymes of the infected cell to carry out the task, due to the unusual nature of producing DNA from RNA.
Industrial drugs that are designed as protease and
reverse-transcriptase inhibitor
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs Enzyme inhibition, inhibit activity of reverse transcriptase, a viral DNA polymerase that is requi ...
s are made such that they target specific sites and sequences within their respective enzymes. However these drugs can quickly become ineffective due to the fact that the gene sequences that code for the protease and the reverse transcriptase quickly mutate. These changes in bases cause specific codons and sites with the enzymes to change and thereby avoid drug targeting by losing the sites that the drug actually targets.
Because reverse transcription lacks the usual
proofreading
Proofreading is the reading of a galley proof or an electronic copy of a publication to find and correct reproduction errors of text or art. Proofreading is the final step in the editorial cycle before publication.
Professional
Traditional ...
of DNA replication, a retrovirus
mutate
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
s very often. This enables the virus to grow
resistant to antiviral pharmaceuticals quickly, and impedes the development of effective
vaccines
A vaccine is a biological preparation that provides active acquired immunity
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and pro ...
and inhibitors for the retrovirus.
One difficulty faced with some retroviruses, such as the Moloney retrovirus, involves the requirement for cells to be actively dividing for transduction. As a result, cells such as neurons are very resistant to infection and transduction by retroviruses. This gives rise to a concern that insertional mutagenesis due to integration into the host genome might lead to cancer or leukemia. This is unlike ''
Lentivirus
''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
'', a genus of ''Retroviridae'', which are able to integrate their RNA into the genome of non-dividing host cells.
Recombination
Two
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
s are packaged into each retrovirus particle, but, after an infection, each virus generates only one
provirus A provirus is a virus genome that is integrated into the DNA of a host cell. In the case of bacterial viruses (bacteriophages), proviruses are often referred to as prophages. However, proviruses are distinctly different from prophages and these ter ...
.
After infection,
reverse transcription
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
occurs and this process is accompanied by
recombination. Recombination involves template strand switching between the two genome copies (copy choice recombination) during reverse transcription. From 5 to 14 recombination events per genome occur at each replication cycle.
Genetic recombination appears to be necessary for maintaining genome integrity and as a repair mechanism for salvaging damaged genomes.
[
]
Transmission
* Cell-to-cell
* Fluids
* Airborne, like the Jaagsiekte sheep retrovirus
Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus which is the causative agent of a contagious lung cancer in sheep, called ovine pulmonary adenocarcinoma.
Natural history
JSRV is the virus that is the cause of the contagious lung tumors ...
.
Provirus
The DNA formed after reverse transcription (the provirus) is longer than the RNA genome because each of the terminals have the U3 - R - U5 sequences called long terminal repeat (LTR). Thus, 5' terminal has the extra U3 sequence, while the other terminal has the U5 sequence. LTRs are able to send signals for vital tasks to be carried out such as initiation of RNA production or management of the rate of transcription. This way, LTRs can control replication, hence, the entire progress of the viral cycle. Although located in the nucleus, the non-integrated retroviral cDNA is a very weak substrate for transcription. For this reason, an integrated provirus is a necessary for permanent and an effective expression of retroviral genes.
This DNA can be incorporated into host genome as a provirus that can be passed on to progeny cells. The retrovirus DNA is inserted at random into the host genome. Because of this, it can be inserted into oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s. In this way some retroviruses can convert normal cells into cancer cells. Some provirus remains latent in the cell for a long period of time before it is activated by the change in cell environment.
Early evolution
Studies of retroviruses led to the first demonstrated synthesis of DNA from RNA templates, a fundamental mode for transferring genetic material that occurs in both eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s and prokaryote
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
s. It has been speculated that the RNA to DNA transcription processes used by retroviruses may have first caused DNA to be used as genetic material. In this model, the RNA world hypothesis
The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence ...
, cellular organisms adopted the more chemically stable DNA when retroviruses evolved to create DNA from the RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
templates.
An estimate of the date of evolution of the foamy-like endogenous retroviruses placed the time of the most recent common ancestor at > .
Gene therapy
Gammaretroviral and lentiviral
''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
vectors for gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
have been developed that mediate stable genetic modification of treated cells by chromosomal integration of the transferred vector genomes. This technology is of use, not only for research purposes, but also for clinical gene therapy aiming at the long-term correction of genetic defects, e.g., in stem and progenitor cells. Retroviral vector particles with tropism for various target cells have been designed. Gammaretroviral and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases. Retroviral mutations can be developed to make transgenic mouse models to study various cancers and their metastatic models.
Cancer
Retroviruses that cause tumor growth include '' Rous sarcoma virus'' and ''mouse mammary tumor virus
Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTL viruses, HI viruses, and BLV. It belongs to the genus ''Betaretrovirus''. MMTV was formerly known as Bittner virus, and previously the "milk factor", referring to t ...
''. Cancer can be triggered by proto-oncogenes that were mistakenly incorporated into proviral DNA or by the disruption of cellular proto-oncogenes. Rous sarcoma virus contains the src gene
Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HCK, ...
that triggers tumor formation. Later it was found that a similar gene in cells is involved in cell signaling, which was most likely excised with the proviral DNA. Nontransforming viruses can randomly insert their DNA into proto-oncogenes, disrupting the expression of proteins that regulate the cell cycle. The promoter of the provirus DNA can also cause over expression of regulatory genes.
Retroviruses can cause diseases such as cancer and immunodeficiency. If viral DNA is integrated into host chromosomes, it can lead to permanent infections. It is therefore important to discover the body's response to retroviruses. Exogenous retroviruses are especially associated with pathogenic diseases. For example, mice have mouse mammary tumor virus (MMTV), which is a retrovirus. This virus passes to newborn mice through mammary milk. When they are 6 months old, the mice carrying the virus get mammary cancer because of the retrovirus. In addition, leukemia virus I (HTLV-1), found in human T cell, has been found in humans for many years. It is estimated that this retrovirus causes leukemia in the ages of 40 and 50. It has a replicable structure that can induce cancer. In addition to the usual gene sequence of retroviruses, HTLV-1 contains a fourth region, PX. This region encodes Tax, Rex, p12, p13 and p30 regulatory proteins. The Tax protein initiates the leukemic process and organizes the transcription of all viral genes in the integrated HTLV proviral DNA.
Classification
Exogenous
Exogenous retroviruses are infectious RNA- or DNA-containing viruses that are transmitted from one organism to another. In the Baltimore classification
Baltimore classification is a system used to classify viruses based on their manner of messenger RNA (mRNA) synthesis. By organizing viruses based on their manner of mRNA production, it is possible to study viruses that behave similarly as a di ...
system, which groups viruses together based on their manner of messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the p ...
synthesis, they are classified into two groups: Group VI: single-stranded RNA viruses with a DNA intermediate in their life cycle, and Group VII: double-stranded DNA viruses with an RNA intermediate in their life cycle.
Group VI viruses
All members of Group VI use virally encoded reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
, an RNA-dependent DNA polymerase, to produce DNA from the initial virion RNA genome. This DNA is often integrated into the host genome, as in the case of retroviruses and pseudoviruses, where it is replicated and transcribed by the host.
Group VI includes:
* Order Ortervirales
''Ortervirales'' is an order that contains all accepted species of single-stranded RNA viruses that replicate through a DNA intermediate (Group VI) and all accepted species of double-stranded DNA viruses (except ''Hepadnaviridae'') that replicat ...
** Family ''Belpaoviridae
''Semotivirus'' is the only genus of viruses in the family ''Belpaoviridae'' (formerly included in the family ''Metaviridae''). Species exist as retrotransposons in a eukaryotic host's genome. BEL/pao transposons are only found in animals.
Spec ...
''
** Family ''Metaviridae
''Metaviridae'' is a family of viruses which exist as Ty3-gypsy LTR retrotransposons in a eukaryotic host's genome. They are closely related to retroviruses: members of the family ''Metaviridae'' share many genomic elements with retroviruses, in ...
''
** Family ''Pseudoviridae
''Pseudoviridae'' is a family of viruses, which includes three genera.
Viruses of the family are actually LTR retrotransposons of the Ty1-copia family. They replicate via structures called virus-like particles (VLPs). VLPs are not infectious l ...
''
** Family ''Retroviridae
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase e ...
'' – Retroviruses, e.g. ''HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
''
** Family ''Caulimoviridae
''Caulimoviridae'' is a family of viruses infecting plants. There are 94 species in this family, assigned to 11 genera. Viruses belonging to the family ''Caulimoviridae'' are termed double-stranded DNA (dsDNA) reverse-transcribing viruses (or pa ...
'' – a VII group virus family (see below)
The family ''Retroviridae'' was previously divided into three subfamilies (''Oncovirinae'', ''Lentivirinae'', and ''Spumavirinae''), but are now divided into two: ''Orthoretrovirinae'' and ''Spumaretrovirinae''. The term oncovirus
An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their RNA virus origin. With the lette ...
is now commonly used to describe a cancer-causing virus. This family now includes the following genera:
* Subfamily ''Orthoretrovirinae
''Orthoretrovirinae'' is a subfamily of viruses belonging to ''Retroviridae'', a family of enveloped viruses that replicate in a host cell through the process of reverse transcription. The subfamily currently includes six genera, of which ''Lent ...
'':
** Genus ''Alpharetrovirus
''Alpharetrovirus'' is a genus of the family Retroviridae. It has type C morphology. Members can cause sarcomas, other tumors, and anaemia of wild and domestic birds and also affect rats.
Species include the Rous sarcoma virus, avian leukosi ...
''; including ''Avian leukosis virus
Avian sarcoma leukosis virus (ASLV) is an endogenous retrovirus that infects and can lead to cancer in chickens; experimentally it can infect other species of birds and mammals. ASLV replicates in chicken embryo fibroblasts, the cells that contr ...
'' and '' Rous sarcoma virus''
** Genus ''Betaretrovirus
''Betaretrovirus'' is a genus of the ''Retroviridae'' family. It has type B or type D morphology. The type B is common for a few exogenous, vertically transmitted and endogenous viruses of mice; some primate and sheep viruses are the type D.
Ex ...
''; including ''Mouse mammary tumour virus
Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTLV, HTL viruses, HIV, HI viruses, and Bovine leukemia virus, BLV. It belongs to the genus ''Betaretrovirus''. MMTV was formerly known as Bittner virus, and previously th ...
''
** Genus ''Gammaretrovirus
Gammaretrovirus is a genus in the ''Retroviridae'' Family (biology), family. Example species are the murine leukemia virus and the feline leukemia virus. They cause various sarcomas, leukemias and immune deficiencies in mammals, reptiles and bird ...
''; including ''Murine leukemia virus
The murine leukemia viruses (MLVs or MuLVs) are retroviruses named for their ability to cause cancer in murine (mouse) hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses. Replicating MLVs have a pos ...
'' and ''Feline leukemia virus
Feline leukemia virus (FeLV) is a retrovirus that infects cats. FeLV can be transmitted from infected cats when the transfer of saliva or nasal secretions is involved. If not defeated by the animal's immune system, the virus weakens the cat's i ...
''
** Genus ''Deltaretrovirus
''Deltaretrovirus'' is a genus of the ''Retroviridae'' family. It consists of exogenous horizontally transmitted viruses found in several groups of mammals.
Examples are the ''Bovine leukemia virus'' and the human T-lymphotropic virus
The hum ...
''; including ''Bovine leukemia virus
Bovine leukemia virus (BLV) is a retrovirus which causes enzootic bovine leukosis in cattle. It is closely related to the human T‑lymphotropic virus type 1 ( HTLV-I). BLV may integrate into the genomic DNA of B‑lymphocytes as a DNA intermedi ...
'' and the cancer-causing ''Human T-lymphotropic virus
The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and ...
''
** Genus ''Epsilonretrovirus
''Epsilonretrovirus'' is a waterborn genus of the ''Retroviridae'' family. It infects fish. The species include ''Walleye dermal sarcoma virus'', and ''Walleye epidermal hyperplasia virus 1
The walleye epidermal hyperplasia viruses are two spec ...
''
** Genus ''Lentivirus
''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
''; including ''Human immunodeficiency virus 1
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey, ...
'' and ''Simian
The simians, anthropoids, or higher primates are an infraorder (Simiiformes ) of primates containing all animals traditionally called monkeys and apes. More precisely, they consist of the parvorders New World monkeys (Platyrrhini) and Catarrhi ...
'' and '' Feline'' immunodeficiency viruses
* Subfamily ''Spumaretrovirinae
''Spumaretrovirinae'', commonly called spumaviruses (, Latin for "foam") or foamyviruses, is a subfamily of the ''Retroviridae'' family. ICTVMaster Species List 2018a v1MSL including all taxa updates since the 2017 release. Fall 2018 (MSL #33) Sp ...
'':
** Genus '' Bovispumavirus''
** Genus '' Equispumavirus''
** Genus '' Felispumavirus''
** Genus '' Prosimiispumavirus''
** Genus '' Simiispumavirus''
Note that according to ICTV 2017, genus ''Spumavirus
''Spumaretrovirinae'', commonly called spumaviruses (, Latin for "foam") or foamyviruses, is a subfamily of the ''Retroviridae'' family. ICTVMaster Species List 2018a v1MSL including all taxa updates since the 2017 release. Fall 2018 (MSL #33) Sp ...
'' has been divided into five genera, and its former type species ''Simian foamy virus
''Simian foamy virus'' (''SFV'') is a species of the genus ''Spumavirus'' that belongs to the family of ''Retroviridae''. It has been identified in a wide variety of primates, including prosimians, New World and Old World monkeys, as well as ap ...
'' is now upgraded to genus ''Simiispumavirus'' with not less than 14 species, including new type species ''Eastern chimpanzee simian foamy virus
Eastern may refer to:
Transportation
*China Eastern Airlines, a current Chinese airline based in Shanghai
*Eastern Air, former name of Zambia Skyways
*Eastern Air Lines, a defunct American airline that operated from 1926 to 1991
*Eastern Air Li ...
''.
Group VII viruses
Both families in Group VII have DNA genomes contained within the invading virus particles. The DNA genome is transcribed into both mRNA, for use as a transcript in protein synthesis, and pre-genomic RNA, for use as the template during genome replication. Virally encoded reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
uses the pre-genomic RNA as a template for the creation of genomic DNA.
Group VII includes:
* Family ''Caulimoviridae
''Caulimoviridae'' is a family of viruses infecting plants. There are 94 species in this family, assigned to 11 genera. Viruses belonging to the family ''Caulimoviridae'' are termed double-stranded DNA (dsDNA) reverse-transcribing viruses (or pa ...
'' — e.g. ''Cauliflower mosaic virus
Cauliflower mosaic virus (CaMV) is a member of the genus ''Caulimovirus'', one of the six genera in the family ''Caulimoviridae'', which are pararetroviruses that infect plants. Pararetroviruses replicate through reverse transcription just like ...
''
* Family ''Hepadnaviridae
''Hepadnaviridae'' is a family of viruses. Humans, apes, and birds serve as natural hosts. There are currently 18 species in this family, divided among 5 genera. Its best-known member is hepatitis B virus. Diseases associated with this family i ...
'' — e.g. ''Hepatitis B virus
''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus ''Orthohepadnavirus'' and a member of the ''Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B.
Disease
Despite there bein ...
''
The latter family is closely related to the newly proposed
* Family '' Nackednaviridae'' — e.g. ''African cichlid nackednavirus
African or Africans may refer to:
* Anything from or pertaining to the continent of Africa:
** People who are native to Africa, descendants of natives of Africa, or individuals who trace their ancestry to indigenous inhabitants of Africa
*** Ethn ...
'' (ACNDV), formerly named ''African cichlid hepatitis B virus'' (ACHBV).[ an]
PDF
/ref>
whilst families ''Belpaoviridae
''Semotivirus'' is the only genus of viruses in the family ''Belpaoviridae'' (formerly included in the family ''Metaviridae''). Species exist as retrotransposons in a eukaryotic host's genome. BEL/pao transposons are only found in animals.
Spec ...
'', ''Metaviridae
''Metaviridae'' is a family of viruses which exist as Ty3-gypsy LTR retrotransposons in a eukaryotic host's genome. They are closely related to retroviruses: members of the family ''Metaviridae'' share many genomic elements with retroviruses, in ...
'', ''Pseudoviridae
''Pseudoviridae'' is a family of viruses, which includes three genera.
Viruses of the family are actually LTR retrotransposons of the Ty1-copia family. They replicate via structures called virus-like particles (VLPs). VLPs are not infectious l ...
'', ''Retroviridae
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase e ...
'', and ''Caulimoviridae
''Caulimoviridae'' is a family of viruses infecting plants. There are 94 species in this family, assigned to 11 genera. Viruses belonging to the family ''Caulimoviridae'' are termed double-stranded DNA (dsDNA) reverse-transcribing viruses (or pa ...
'' constitute the order ''Ortervirales
''Ortervirales'' is an order that contains all accepted species of single-stranded RNA viruses that replicate through a DNA intermediate (Group VI) and all accepted species of double-stranded DNA viruses (except ''Hepadnaviridae'') that replicat ...
''.
Endogenous
Endogenous retroviruses are not formally included in this classification system, and are broadly classified into three classes, on the basis of relatedness to exogenous genera:
* Class I are most similar to the gammaretroviruses
* Class II are most similar to the betaretroviruses and alpharetroviruses
* Class III are most similar to the spumaviruses.
Controversy
Retroviruses have been the focus of several recent claims and assertions which have been largely discredited by the science community. An initial study in 2009 seemed to make new findings which might change some of the established knowledge on this topic. However, although later research disproved some of the claims made about retroviruses, there are several controversial figures who continue to make claims which overall are considered to not have any valid basis or consensus in support of these claims.
Treatment
Antiretroviral drug
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple ...
s are medications for the treatment of infection by retroviruses, primarily HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
. Different classes of antiretroviral drugs act on different stages of the HIV life cycle
Life cycle, life-cycle, or lifecycle may refer to:
Science and academia
*Biological life cycle, the sequence of life stages that an organism undergoes from birth to reproduction ending with the production of the offspring
*Life-cycle hypothesis, ...
. Combination of several (typically three or four) antiretroviral drugs is known as highly active antiretroviral therapy (HAART).
Treatment of veterinary retroviruses
''Feline leukemia virus
Feline leukemia virus (FeLV) is a retrovirus that infects cats. FeLV can be transmitted from infected cats when the transfer of saliva or nasal secretions is involved. If not defeated by the animal's immune system, the virus weakens the cat's i ...
'' and ''Feline immunodeficiency virus
Feline immunodeficiency virus (FIV) is a '' Lentivirus'' that affects cats worldwide, with 2.5% to 4.4% of felines being infected.
FIV was first isolated in 1986, by Niels C Pedersen and Janet K. Yamamoto at the UC Davis School of Veterina ...
'' infections are treated with biologics
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, th ...
, including the only immunomodulator currently licensed for sale in the United States, Lymphocyte T-Cell Immune Modulator Lymphocyte T-cell immunomodulator (LTCI) is an immune regulating polypeptide, which is a potent regulator of CD-4 lymphocyte production and function. It increases lymphocyte numbers and interleukin-2 (IL-2) production in animals. It is extracted fr ...
(LTCI).
Notes
References
Further reading
*
*
*
External links
ViralZone
A Swiss Institute of Bioinformatics
The SIB Swiss Institute of Bioinformatics is an academic not-for-profit foundation which federates bioinformatics activities throughout Switzerland.
The institute was established on 30 March 1998 and its mission is to provide core bioinfor ...
resource for all viral families, providing general molecular and epidemiological information (follow links for ''"Retro-transcribing viruses"'')
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Retrovirology
Scientific journal
From Kimball's ''Biology'' (online biology textbook pages)
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Ortervirales
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