Lentivirus
Encyclopedia
Lentivirus is a genus
of slow
virus
es of the Retroviridae family
, characterized by a long incubation period
. Lentiviruses can deliver a significant amount of genetic
information into the DNA
of the host cell
and have the unique ability among retroviruses of being able to replicate in non-dividing cells, so they are one of the most efficient methods of a gene delivery vector
. HIV, SIV
, and FIV
are all examples of lentiviruses.
of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, cats, and cattle). The primate
lentiviruses are distinguished by the use of CD4
protein as receptor and the absence of dUTPase. Some groups have cross-reactive gag
antigens (e.g., the ovine, caprine and feline
lentiviruses). Antibodies to gag antigens in lions and other large felids indicate the existence of other viruses related to FIV and the ovine/caprine lentiviruses. Description is on taxonomic level of genus.
make the surface appear rough, or tiny spikes
(about 8 nm) may be dispersed evenly over the surface. The nucleocapsids (cores) are isometric. The nucleoids
are concentric and rod-shaped, or shaped like a truncated cone.
(LTR) is about 600nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.
Viral proteins involved in early stages of replication include Reverse Transcriptase
and Integrase
. Reverse Transcriptase is the virally encoded RNA-dependent DNA polymerase. The enzyme uses the viral RNA genome as a template for the synthesis of a complementary DNA copy. Reverse transcriptase also has RNaseH activity for destruction of the RNA-template. Integrase binds both the viral cDNA generated by reverse transcriptase and the host DNA. Integrase processes the LTR before inserting the viral genome into the host DNA.
Although transmission is generally via infectious particles, lentiviruses are capable of infecting neighboring cells in direct contact with the host cells, without having to form extracellular particles.
determinants are type-specific and group-specific. Antigen determinants that possess type-specific reactivity are found on the envelope. Antigen determinants that possess type-specific reactivity and are involved in antibody mediated neutralization are found on the glycoproteins. Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of this taxon
is infrequently based on their antigenic properties.
Classed as having class C morphology
systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference
technology in high-throughput formats. The expression of short-hairpin RNA (shRNA) reduces the expression of a specific gene, thus allowing researchers to examine the necessity and effects of a given gene in a model system. These studies can be a precursor to the development of novel drugs which aim to block a gene-product to treat diseases.
Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated in human hemophilia. Lentiviral infection have advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity.
Lentiviruses have also been successfully used for transfection
of diabetic mice with the gene
encoding PDGF (platelet-derived growth factor), a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies.
Gammaretroviral
and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases.
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
of slow
Slow virus
A slow virus is a virus, or a viruslike agent, etiologically associated with a disease having a long incubation period of months to years with a gradual onset frequently terminating in severe illness and/or death....
virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es of the Retroviridae family
Family (biology)
In biological classification, family is* a taxonomic rank. Other well-known ranks are life, domain, kingdom, phylum, class, order, genus, and species, with family fitting between order and genus. As for the other well-known ranks, there is the option of an immediately lower rank, indicated by the...
, characterized by a long incubation period
Incubation period
Incubation period is the time elapsed between exposure to a pathogenic organism, a chemical or radiation, and when symptoms and signs are first apparent...
. Lentiviruses can deliver a significant amount of genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
information into the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
of the host cell
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
and have the unique ability among retroviruses of being able to replicate in non-dividing cells, so they are one of the most efficient methods of a gene delivery vector
Vector (molecular biology)
In molecular biology, a vector is a DNA molecule used as a vehicle to transfer foreign genetic material into another cell. The four major types of vectors are plasmids, viruses, cosmids, and artificial chromosomes...
. HIV, SIV
Simian immunodeficiency virus
Simian immunodeficiency virus , also known as African Green Monkey virus and also as Monkey AIDS is a retrovirus able to infect at least 33 species of African primates...
, and FIV
Feline immunodeficiency virus
Feline immunodeficiency virus is a lentivirus that affects domesticated housecats worldwide and is the causative agent of feline AIDS. From 2.5% up to 4.4% of cats worldwide are infected with FIV...
are all examples of lentiviruses.
Classification
Five serogroupsSerotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...
of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, cats, and cattle). The primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
lentiviruses are distinguished by the use of CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
protein as receptor and the absence of dUTPase. Some groups have cross-reactive gag
Group-specific antigen
Group-specific antigen is the genetic material that codes for the core structural proteins of a retrovirus.It comprises part of the gag-onc fusion protein.-Gag in HIV:...
antigens (e.g., the ovine, caprine and feline
Felidae
Felidae is the biological family of the cats; a member of this family is called a felid. Felids are the strictest carnivores of the thirteen terrestrial families in the order Carnivora, although the three families of marine mammals comprising the superfamily pinnipedia are as carnivorous as the...
lentiviruses). Antibodies to gag antigens in lions and other large felids indicate the existence of other viruses related to FIV and the ovine/caprine lentiviruses. Description is on taxonomic level of genus.
Morphology
The virions are enveloped, slightly pleomorphic, spherical and measure 80–100 nm in diameter. Projections of envelopeViral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
make the surface appear rough, or tiny spikes
Peplomer
A peplomer is a glycoprotein spike on a viral capsid or viral envelope. These protrusions will only bind to certain receptors on the host cell: they are essential for both host specificity and viral infectivity...
(about 8 nm) may be dispersed evenly over the surface. The nucleocapsids (cores) are isometric. The nucleoids
Nucleoid
The nucleoid is an irregularly-shaped region within the cell of a prokaryote that contains all or most of the genetic material. In contrast to the nucleus of a eukaryotic cell, it is not surrounded by a nuclear membrane. The genome of prokaryotic organisms generally is a circular, double-stranded...
are concentric and rod-shaped, or shaped like a truncated cone.
Genome organization and replication
Features of the genome: infectious viruses have 3 main genes coding for the viral proteins in the order: 5´-gag-pol-env-3´. There are additional genes (also called accessory genes) depending on the virus (e.g., for HIV-1: vif, vpr, vpu, tat, rev, nef) whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. The Long terminal repeatLong terminal repeat
Long terminal repeats are sequences of DNA that repeat hundreds or thousands of times. They are found in retroviral DNA and in retrotransposons, flanking functional genes...
(LTR) is about 600nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.
Viral proteins involved in early stages of replication include Reverse Transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
and Integrase
Integrase
Retroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
. Reverse Transcriptase is the virally encoded RNA-dependent DNA polymerase. The enzyme uses the viral RNA genome as a template for the synthesis of a complementary DNA copy. Reverse transcriptase also has RNaseH activity for destruction of the RNA-template. Integrase binds both the viral cDNA generated by reverse transcriptase and the host DNA. Integrase processes the LTR before inserting the viral genome into the host DNA.
Although transmission is generally via infectious particles, lentiviruses are capable of infecting neighboring cells in direct contact with the host cells, without having to form extracellular particles.
Antigenic properties
Serological Relationships: AntigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
determinants are type-specific and group-specific. Antigen determinants that possess type-specific reactivity are found on the envelope. Antigen determinants that possess type-specific reactivity and are involved in antibody mediated neutralization are found on the glycoproteins. Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of this taxon
Taxon
|thumb|270px|[[African elephants]] form a widely-accepted taxon, the [[genus]] LoxodontaA taxon is a group of organisms, which a taxonomist adjudges to be a unit. Usually a taxon is given a name and a rank, although neither is a requirement...
is infrequently based on their antigenic properties.
Biological
- Symptoms and host range: The virus' hosts are found in the orders Primates, Perissodactyla, CarnivoraCarnivoraThe diverse order Carnivora |Latin]] carō "flesh", + vorāre "to devour") includes over 260 species of placental mammals. Its members are formally referred to as carnivorans, while the word "carnivore" can refer to any meat-eating animal...
, and Artiodactyla (all within domain EucaryaEucaryaEucarya may refer to:*Eukaryotes, organisms whose cells contain complex structures inside the membranes.*Eucarya, a formerly recognized genus of flowering plants that is now considered to be part of the genus Santalum....
, kingdom Animalia, phylum Chordata, subphylum Vertebrata, and class Mammalia.) - TransmissionTransmission (medicine)In medicine and biology, transmission is the passing of a communicable disease from an infected host individual or group to a conspecific individual or group, regardless of whether the other individual was previously infected...
: Transmitted by means not involving a vector. - Geographic distribution: Worldwide.
Physicochemical and physical properties
- General
- Buoyant density 1.16–1.18 g cm−3 in sucroseSucroseSucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
- Virions sensitive to heat, detergentDetergentA detergent is a surfactant or a mixture of surfactants with "cleaning properties in dilute solutions." In common usage, "detergent" refers to alkylbenzenesulfonates, a family of compounds that are similar to soap but are less affected by hard water...
s, and formaldehydeFormaldehydeFormaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers... - Infectivity not affected by irradiation
- Buoyant density 1.16–1.18 g cm−3 in sucrose
Classed as having class C morphology
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
- Nucleic AcidNucleic acidNucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
- Virions contain 2 % nucleic acidNucleic acidNucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
- GenomeGenomeIn modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
consists of a dimer - Virions contain one molecule of (each) linear positive-sense single stranded RNARNARibonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. - Total genome length is of one monomerMonomerA monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
9200 nt - Genome sequence has terminal repeated sequences; long terminal repeatLong terminal repeatLong terminal repeats are sequences of DNA that repeat hundreds or thousands of times. They are found in retroviral DNA and in retrotransposons, flanking functional genes...
s (LTR) (of about 600 nt - The 5' end of the genome has a cap
- Cap sequence of type 1 m7G5ppp5'GmpNp
- 3' end of each monomer has a poly (A) tract; 3'-terminus has a tRNA-like structure (and accepts lysin)
- Encapsidated nucleic acidNucleic acidNucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
are solely genomic - 2 copies packed per particle (held together by hydrogen bonds to form a dimer).
- Virions contain 2 % nucleic acid
- There are 11 proteins
- Virions contain 60 % protein
- Five (major)structural virion proteins have been found so far
- Listed here by protein size:
- Largest 120000 Da (Daltons). Gp120 glycosylateGlycosylationGlycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
d surface envelope protein SU, encoded by the viral gene env - 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
- 3rd largest 24000 Da. P24 non-glycosylated capsidCapsidA capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
protein CA. - 4th largest 17000 Da. P17 non-glycosylated matrixNuclear matrixIn biology, the nuclear matrix is the network of fibres found throughout the inside of a cell nucleus and is somewhat analogous to the cell cytoskeleton...
protein MA. - 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
- Proteins MA, CA and NC (4,3 and 5)are encoded by the gag gene.
- Largest 120000 Da (Daltons). Gp120 glycosylate
- The envelope proteins SU and TM are glycosylated in at least some lentiviruses (HIV, SIV), if not all of them. Glycosylation seems to play a structural role in the concealment and variation of antigenic sites necessary for the host to mount an immune system response.
- Listed here by protein size:
- Usually four (4) non-structural proteins found, or three (3) non-structural proteins found (in the primate lentiviruses).
- Protein size 66000 Da. Reverse transcriptaseReverse transcriptaseIn the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
encoded by the pol gene. - Protein size of 2nd largest 32000 Da. IntegraseIntegraseRetroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
IN also encoded by the pol gene. - Protein size of 3rd 14000 Da. ProteaseProteaseA protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
- Protein size 66000 Da. Reverse transcriptase
- Lipids: Virions contain 35 % lipidLipidLipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
. - Carbohydrates: Other compounds detected in the particles 3% carbohydrates.
Practical applications
Lentivirus is primarily a research tool used to introduce a gene product into in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
technology in high-throughput formats. The expression of short-hairpin RNA (shRNA) reduces the expression of a specific gene, thus allowing researchers to examine the necessity and effects of a given gene in a model system. These studies can be a precursor to the development of novel drugs which aim to block a gene-product to treat diseases.
Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated in human hemophilia. Lentiviral infection have advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity.
Lentiviruses have also been successfully used for transfection
Transfection
Transfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...
of diabetic mice with the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encoding PDGF (platelet-derived growth factor), a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies.
Gammaretroviral
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases.