''Lentivirus'' is a
genus
Genus ( plural genera ) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biological classification, genus com ...
of
retrovirus
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 ...
es that cause chronic and deadly diseases characterized by long
incubation period
Incubation period (also known as the latent period or latency period) is the time elapsed between exposure to a pathogenic organism, a chemical, or radiation, and when symptoms and signs are first apparent. In a typical infectious disease, the i ...
s, in humans and other mammalian species.
The genus includes the
human immunodeficiency virus
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the ...
(HIV), which causes
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 ...
. Lentiviruses are distributed worldwide, and are known to be hosted in apes,
cows
Cattle (''Bos taurus'') are large, domesticated, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus ''Bos''. Adult females are referred to as cows and adult ma ...
, goats, horses, cats, and sheep as well as several other mammals.
Lentiviruses can integrate a significant amount of
viral complementary DNA
In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a spe ...
into the
DNA of the
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 ...
and can efficiently infect nondividing cells, so they are one of the most efficient methods of
gene delivery
Gene delivery is the process of introducing foreign genetic material, such as DNA or RNA, into host cells. Gene delivery must reach the genome of the host cell to induce gene expression. Successful gene delivery requires the foreign gene delive ...
. They can become
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
, integrating their genome into the host
germline
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 ...
genome, so that the virus is henceforth inherited by the host's descendants.
Classification
Five
serogroups of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, domestic cats, and cattle). The
primate
Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...
lentiviruses are distinguished by the use of
CD4
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
protein as a
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
and the absence of
dUTPase
In Enzymology, a dUTP diphosphatase () is an enzyme that catalysis, catalyzes the chemical reaction
:dUTP + H2O \rightleftharpoons dUMP + diphosphate
Thus, the two substrate (biochemistry), substrates of this enzyme are Deoxyuridine triphosph ...
. Some groups have cross-reactive
gag
A gag is usually an item or device designed to prevent speech, often as a restraint device to stop the subject from calling for help and keep its wearer silent. This is usually done by blocking the mouth, partially or completely, or attempting ...
antigens
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
(e.g., the
ovine
Sheep or domestic sheep (''Ovis aries'') are domesticated, ruminant mammals typically kept as livestock. Although the term ''sheep'' can apply to other species in the genus ''Ovis'', in everyday usage it almost always refers to domesticated s ...
,
caprine, and
feline lentiviruses).
Antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
to gag antigens in lions and other large felines indicate the existence of another yet to be identified virus related to feline lentivirus and the ovine/caprine lentiviruses.
Morphology
The
virions
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 ...
are enveloped, slightly
pleomorphic, spherical and measure 80–100 nm in diameter. Projections of
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 ...
make the surface appear rough, or tiny
spikes
The SPIKES protocol is a method used in clinical medicine to break bad news to patients and families. As receiving bad news can cause distress and anxiety, clinicians need to deliver the news carefully. By using the SPIKES method for introducing a ...
(about 8 nm) may be dispersed evenly over the surface. The
nucleocapsid
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 ...
s (cores) are isometric. The
nucleoid
The nucleoid (meaning ''nucleus-like'') is an irregularly shaped region within the prokaryotic cell that contains all or most of the genetic material. The chromosome of a prokaryote is circular, and its length is very large compared to the cell dim ...
s are concentric and rod-shaped, or shaped like a truncated cone.
Genome organization and replication
As with all retroviruses, lentiviruses have ''gag'', ''pol'' and ''env'' genes, coding for viral proteins in the order: 5´-''gag''-''pol''-''env''-3´. Unlike other retroviruses, however, lentiviruses have two
regulatory genes
A regulator gene, regulator, or regulatory gene is a gene involved in controlling the gene expression, expression of one or more other genes. Regulatory sequences, which encode regulatory genes, are often Directionality (molecular biology), at the ...
,
''tat'' and
''rev''. They may also have additional accessory genes depending on the virus (e.g., for HIV-1:
''vif'', ''
vpr
Vpr is a Human immunodeficiency virus gene and protein product.
Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for ...
'', ''
vpu
VPU may refer to:
Technology
* Video processing unit and visual processing unit, related to graphics processing units
* Vision processing unit, a class of processor intended for accelerating machine vision tasks
* Vector processing unit, a specia ...
'',
''nef'') whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. The
Long terminal repeat
A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or ...
(LTR) is about 600
nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.
Retroviruses carry specific proteins within their capsids, which typically associate with the RNA genome. These proteins are typically involved in the early stages of genome replication, and include
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, ...
and
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 ...
. 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. Tat acts as a trans-activator during transcription to enhance initiation and elongation. The Rev responsive element acts post-transcriptionally, regulating mRNA splicing and transport to the cytoplasm.
Proteome
The lentiviral proteome consists of five major structural proteins and 3-4 non-structural proteins (3 in the primate lentiviruses).
Structural proteins listed by size:
#
Gp120
Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1988. The 120 in its name comes from ...
surface envelope protein SU, encoded by the viral gene ''
env
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, ...
''. 120000 Da (
Dalton
Dalton may refer to:
Science
* Dalton (crater), a lunar crater
* Dalton (program), chemistry software
* Dalton (unit) (Da), the atomic mass unit
* John Dalton, chemist, physicist and meteorologist
Entertainment
* Dalton (Buffyverse), minor cha ...
s).
#
Gp41
Gp41 also known as glycoprotein 41 is a subunit of the envelope protein complex of retroviruses, including human immunodeficiency virus (HIV). Gp41 is a transmembrane protein that contains several sites within its ectodomain that are required fo ...
transmembrane envelope protein TM, also encoded by the viral gene ''env''. 41000 Da.
#
P24 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 ...
protein CA, encoded by the viral gene ''gag''. 24000 Da.
# P17
matrix
Matrix most commonly refers to:
* ''The Matrix'' (franchise), an American media franchise
** ''The Matrix'', a 1999 science-fiction action film
** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchis ...
protein MA, also encoded by ''gag''. 17000 Da.
# P7/P9 capsid protein NC, also encoded by ''gag''. 7000-11000 Da.
The
envelope protein
A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes.
Numerous human pathogenic viruses in circulation are encase ...
s 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.
Enzymes:
#
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, ...
RT encoded by the ''pol'' gene. Protein size 66000 Da.
#
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 ...
IN also encoded by the ''pol'' gene. Protein size 32000 Da.
#
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 encoded by the ''pro'' gene (part of ''pol'' gene in some viruses).
#
dUTPase
In Enzymology, a dUTP diphosphatase () is an enzyme that catalysis, catalyzes the chemical reaction
:dUTP + H2O \rightleftharpoons dUMP + diphosphate
Thus, the two substrate (biochemistry), substrates of this enzyme are Deoxyuridine triphosph ...
DU encoded by the ''pro'' gene (part of ''pol'' gene in some viruses), the role of which is still unknown. Protein size 14000 Da.
Gene regulatory proteins:
#
Tat: main trans-activator
#
Rev: important for synthesis of major viral proteins
Accessory proteins:
#
Nef: negative factor
#
Vpr
Vpr is a Human immunodeficiency virus gene and protein product.
Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for ...
: regulatory protein
#
Vif: APOBEC3 inhibitor
#
Vpu
VPU may refer to:
Technology
* Video processing unit and visual processing unit, related to graphics processing units
* Vision processing unit, a class of processor intended for accelerating machine vision tasks
* Vector processing unit, a specia ...
/
Vpx
VPX (Virtual Path Cross-Connect), also known as VITA 46, refers to a set of standards for connecting components of a computer (known as a computer bus), commonly used by defense contractors.
Some are ANSI standards such as ANSI/VITA 46.0–2019.
...
: unique to each type of HIV
# p6: part of gag
Antigenic properties
Serological relationships:
Antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
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
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
. 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
In biology, a taxon (back-formation from ''taxonomy''; plural taxa) is a group of one or more populations of an organism or organisms seen by taxonomists to form a unit. Although neither is required, a taxon is usually known by a particular nam ...
is infrequently based on their antigenic properties.
Epidemiology
* Symptoms and host range: the virus's hosts are found in the orders
Primates
Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...
(humans, apes and monkeys),
Carnivora
Carnivora is a Clade, monophyletic order of Placentalia, placental mammals consisting of the most recent common ancestor of all felidae, cat-like and canidae, dog-like animals, and all descendants of that ancestor. Members of this group are f ...
(cats, dogs and other carnivores),
Perissodactyla and
Artiodactyla
The even-toed ungulates (Artiodactyla , ) are ungulates—hoofed animals—which bear weight equally on two (an even number) of their five toes: the third and fourth. The other three toes are either present, absent, vestigial, or pointing poster ...
(single and double-toed hooved mammals).
*
Transmission
Transmission may refer to:
Medicine, science and technology
* Power transmission
** Electric power transmission
** Propulsion transmission, technology allowing controlled application of power
*** Automatic transmission
*** Manual transmission
*** ...
: transmitted by means not involving a
vector
Vector most often refers to:
*Euclidean vector, a quantity with a magnitude and a direction
*Vector (epidemiology), an agent that carries and transmits an infectious pathogen into another living organism
Vector may also refer to:
Mathematic ...
.
* Geographic distribution: worldwide.
Physicochemical and physical properties
* General
**
Buoyant
Buoyancy (), or upthrust, is an upward force exerted by a fluid that opposes the weight of a partially or fully immersed object. In a column of fluid, pressure increases with depth as a result of the weight of the overlying fluid. Thus the pr ...
density 1.16–1.18 g cm
−3 in
sucrose
Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula .
For human consumption, sucrose is extracted and refined ...
** Virions sensitive to heat,
detergent
A detergent is a surfactant or a mixture of surfactants with cleansing properties when in dilute solutions. There are a large variety of detergents, a common family being the alkylbenzene sulfonates, which are soap-like compounds that are more ...
s, and
formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
** Infectivity not affected by UV irradiation
Classed as having ''class C''
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, ...
*
Nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
** Virions contain 2%
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
**
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 ...
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 ( ...
** Virions contain one molecule of (each) linear positive-sense 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 ...
.
** Total genome length is of one
monomer
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
ranges from 8k-10k nt (depending on the virus).
** Genome sequence has terminal repeated sequences;
long terminal repeat
A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or ...
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.
** 2 copies packed per particle (held together by Watson-Crick baseparing to form a dimer).
* There are 11 proteins
** Virions contain 60% protein
** Five (major)structural virion proteins have been found so far
*
Lipids
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
: Virions contain 35%
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
.
*
Carbohydrates
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
: Other compounds detected in the particles 3% carbohydrates.
Use as gene delivery vectors
Lentivirus is primarily a research tool used to introduce a gene product into
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
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 (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by o ...
technology in high-throughput formats. Conversely, lentivirus are also used to stably over-express certain genes, thus allowing researchers to examine the effect of increased gene expression in a model system.
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
Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, ...
is corrected by expressing wild-type platelet-
factor VIII
Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8'' gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. ...
, the gene that is mutated in human hemophilia. Lentiviral infection has advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a
transgene
A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
, and low immunogenicity.
Lentiviruses have also been successfully used for
transduction of diabetic mice with the
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
encoding
PDGF
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
(platelet-derived growth factor), a therapy being considered for use in humans. Finally, lentiviruses have been also used to elicit an immune response against tumor antigens.
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.
See also
*
Visna virus
''Visna-maedi virus'' (also known as ''Visna virus'', ''Maedi-visna virus'' and ''Ovine lentivirus'') from the genus ''Lentivirus'' and subfamily ''Orthoretrovirinae'', is a retrovirus that causes encephalitis and chronic pneumonitis in sheep. I ...
Notes
References
*
*
Further reading
ICTV taxonomy of ''Lentivirus''*
*
External links
{{Authority control
*
Virotherapy
Virus genera