Retroviridae is a family of enveloped viruses that replicate in a host cell through the
process of reverse transcription. A retrovirus is a single-stranded RNA virus that stores
its nucleic acid in the form of an mRNA genome and targets a host cell as an obligate parasite.
Once inside the host cell cytoplasm, the virus uses its own reverse transcriptase enzyme
to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro. This new
DNA is then incorporated into the host cell genome by an integrase enzyme, at which point
the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as
part of its own genome, translating and transcribing the viral genes along with the cell's own
genes, producing the proteins required to assemble new copies of the virus. It is difficult
to detect the virus until it has infected the host. At that point, the infection will
persist indefinitely. In most viruses, DNA is transcribed into RNA,
and then RNA is translated into protein. However, retroviruses function differently – their
RNA is reverse-transcribed into DNA, which is integrated into the host cell's genome,
and then undergoes the usual transcription and translational processes to express the
genes carried by the virus. So, the information contained in a retroviral gene is used to
generate the corresponding protein via the sequence: RNA → DNA → RNA → polypeptide.
This extends the fundamental process identified by Francis Crick,, in which the sequence is:
DNA → RNA → peptide,. Retroviruses are proving to be valuable research
tools in molecular biology and have been used successfully in gene delivery systems.
Structure Virions of retroviruses consist of enveloped
particles about 100 nm in diameter. The virions also contain two identical single-stranded
RNA molecules 7–10 kilobases in length. Although virions of different retroviruses
do not have the same morphology or biology, all the virion components are very similar.
The main virion components are: Envelope: composed of lipids as well as glycoprotein
encoded by the env gene. RNA: consists of a dimer RNA. It has a cap
at the 5' end and a poly(A) tail at the 3' end. The RNA genome also has terminal noncoding
regions, which are important in replication, and internal regions that encode virion proteins
for gene expression. 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 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 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 3 regions, which are PPT, U3, and R. The PPT is a primer
for plus-strand DNA synthesis during reverse transcription. U3 is a sequence between PPT
and R, which serves as a signal that the provirus can use in transcription. R is the terminal
repeated sequence at 3' end. Proteins: consisting of gag proteins, protease,
pol proteins and env proteins. Group-specific antigen proteins are major components of the
viral capsid, which are about 2000–4000 copies per virion. Protease is expressed differently
in different viruses. It functions in proteolytic cleavages during virion maturation to make
mature gag and pol proteins. Pol proteins are responsible for synthesis of viral DNA
and integration into host DNA after infection. Finally, env proteins play a role in association
and entry of virion into the host cell. Possessing a functional copy of an env gene is what makes
retroviruses distinct from retroelements. The env gene serves three distinct functions:
enabling the retrovirus to enter/exit host cells through endosomal membrane trafficking,
protection from the extracellular environment via the lipid bilayer, and the ability to
enter cells. The ability of the retrovirus to bind to its target host cell using specific
cell-surface receptors is given by the surface component of the env, while the ability of
the retrovirus to enter the cell via membrane fusion is imparted by the membrane-anchored
trans-membrane component. Thus the env protein is what enables the retrovirus to be infectious.
Multiplication
When retroviruses have integrated their own genome into the germ line, their genome is
passed on to a following generation. These endogenous retroviruses, contrasted with exogenous
ones, now make up 5-8% of the human genome. Most insertions have no known function and
are often referred to as "junk DNA". However, many endogenous retroviruses play important
roles in host biology, such as control of gene transcription, cell fusion during placental
development in the course of the germination of an embryo, and resistance to exogenous
retroviral infection. Endogenous retroviruses have also received special attention in the
research of immunology-related pathologies, such as autoimmune diseases like multiple
sclerosis, 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 transcribes RNA into DNA. The term "retro"
in retrovirus refers to this reversal of the central dogma of molecular biology. Reverse
transcriptase activity outside of retroviruses has been found in almost all eukaryotes, enabling
the generation and insertion of new copies of retrotransposons 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. For example,
the gag gene is translated into molecules of the capsid protein, the pol gene is translated
into molecules of reverse transcriptase, and the env gene is translated into molecules
of the envelope protein. It is important to note that a retrovirus must "bring" its own
reverse transcriptase in its capsid, 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 inhibitors 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 of DNA replication, a retrovirus
mutates very often. This enables the virus to grow resistant to antiviral pharmaceuticals
quickly, and impedes the development of effective vaccines and inhibitors for the retrovirus.
One drawback of 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. There is concern that insertional
mutagenesis due to integration into the host genome might lead to cancer or leukemia. This
is unlike Lentivirus, a genus of Retroviridae, which are able to integrate their RNA into
the genome of non-dividing host cells. Transmission
Cell-to-cell Fluids
Airborne, like the Jaagsiekte sheep retrovirus. Genes
Retrovirus genomes commonly contain these three open reading frames that encode for
proteins that can be found in the mature virus: group-specific antigen codes for core and
structural proteins of the virus; polymerase codes for reverse transcriptase,
protease and integrase; and, envelope codes for the retroviral coat proteins.
Provirus 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 oncogenes. 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 eukaryotes and prokaryotes. 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, cellular organisms adopted the more chemically
stable DNA when retroviruses evolved to create DNA from the RNA templates.
Gene therapy Gammaretroviral and lentiviral vectors for
gene therapy 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. Cancer
Retroviruses that cause tumor growth include Rous sarcoma virus and Mouse mammary tumor
virus. 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 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. Classification
Exogenous These are infectious RNA-containing viruses
which are transmitted from human to human. The following genera are included here:
Genus Alpharetrovirus; type species: Avian leukosis virus; others include Rous sarcoma
virus Genus Betaretrovirus; type species: Mouse
mammary tumour virus Genus Gammaretrovirus; type species: Murine
leukemia virus; others include Feline leukemia virus
Genus Deltaretrovirus; type species: Bovine leukemia virus; others include the cancer-causing
Human T-lymphotropic virus Genus Epsilonretrovirus; type species: Walleye
dermal sarcoma virus Genus Lentivirus; type species: Human immunodeficiency
virus 1; others include Simian, Feline immunodeficiency viruses
Genus Spumavirus; type species: Simian foamy virus
These were previously divided into three subfamilies, but are now divided into two: Orthoretrovirinae
and Spumaretrovirinae. The term oncovirus is now commonly used to describe a cancer-causing
virus. Retroviruses were in 2 groups of the Virus_classification#Baltimore_classification.
Group VI viruses All members of Group VI use virally encoded
reverse transcriptase, 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: Family Metaviridae
Family Pseudoviridae Family Retroviridae — Retroviruses, e.g.
HIV 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 uses the pre-genomic RNA as a template for the creation of genomic
DNA. Group VII includes:
Family Hepadnaviridae — e.g. Hepatitis B virus
Family Caulimoviridae — e.g. Cauliflower mosaic virus
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.
Treatment Antiretroviral drugs are medications for the
treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs
act on different stages of the HIV life cycle. Combination of several antiretroviral drugs
is known as highly active anti-retroviral therapy.
Treatment of veterinary retroviruses Feline leukemia virus and Feline immunodeficiency
virus infections are treated with biologics, including the only immunomodulator currently
licensed for sale in the United States, Lymphocyte T-Cell Immune Modulator.
References
External links ViralZone A Swiss Institute of Bioinformatics
resource for all viral families, providing general molecular and epidemiological information
Retrovirus Animation Retrovirology Scientific journal
Retrovirus life cycle chapter From Kimball's Biology
Coffin, John M; Varmus, Harold E, eds.. Retroviruses. Cold Spring Harbor Laboratory. ISBN 0-87969-571-4.
NBK19376. Specter, Michael. "Annals of Science: Darwin's
Surprise". The New Yorker.