Genetically modified virus

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A genetically modified virus is a virus that has been altered or generated using biotechnology methods, and remains capable of infection. Genetic modification involves the directed insertion, deletion, artificial synthesis or change of nucleotide bases in viral genomes. Genetically modified viruses are mostly generated by the insertion of foreign genes intro viral genomes for the purposes of biomedical, agricultural, bio-control, or technological objectives. The terms genetically modified virus and genetically engineered virus are used synonymously.

Contents

General usage

Genetically modified viruses are generated through genetic modification, which involves the directed insertion, deletion, artificial synthesis, or change of nucleotide sequences in viral genomes using biotechnological methods. While most dsDNA viruses have single monopartite genomes, many RNA viruses have multipartite genomes, it is not necessary for all parts of a viral genome to be genetically modified for the virus to be considered a genetically modified virus. Infectious viruses capable of infection that are generated through artificial gene synthesis of all, or part of their genomes (for example based on inferred historical sequences) may also be considered as genetically modified viruses. Viruses that are changed solely through the action of spontaneous mutations, recombination or reassortment events (even in experimental settings), are not generally considered to be genetically modified viruses.

Viruses are generally modified so they can be used as vectors for inserting new genetic information into a host organism or altering its preexisting genetic material. This can be achieved in at least three processes :

  1. Integration of all, or parts, of a viral genome into the host's genome (e.g. into its chromosomes). When the whole genetically modified viral genome is integrated it is then referred to as a genetically modified provirus. Where DNA or RNA which that has been packaged as part of a virus particle, but may not necessarily contain any viral genes, becomes integrated into a hosts genome this process is known as transduction.
  2. Maintenance of the viral genome within host cells but not as an integrated part of the host's genome.
  3. Where genes necessary for genome editing have been placed into the viral genome using biotechnology methods, [1] editing of the host's genome is possible. This process does not require the integration of viral genomes into the host's genome.

None of these three processes are mutually exclusive. Where only process 2. occurs and it results in the expression of a genetically modified gene this will often be referred to as a transient expression approach.

The capacity to infect host cells or tissues is a necessary requirement for all applied uses of genetically modified viruses. However, a capacity for viral transmission (the transfer of infections between host individuals), is either not required or is considered undesirable for most applications. Only in a small minority of proposed uses is viral transmission considered necessary or desirable, an example is transmissible vaccines. [2] [3] This is because transmissibility considerably complicates to efforts monitor, control, or contain the spread of viruses. [4]

History

In 1972, the earliest report of the insertion of a foreign sequence into a viral genome was published, when Paul Berg used the EcoRI restriction enzyme and DNA ligases to create the first ever recombinant DNA molecules. [5] This was achieved by joining DNA from the monkey SV40 virus with that of the lambda virus. However, it was not established that either of the two viruses were capable of infection or replication.

In 1974, the first report of a genetically modified virus that could also replicate and infect was submitted for publication by Noreen Murray and Kenneth Murray. [6] Just two months later in August 1974, Marjorie Thomas, John Cameron and Ronald W. Davis submitted a report for publication of a similar achievement. [7]

Collectively, these experiments represented the very start of the development of what would eventually become known as biotechnology or recombinant DNA methods.

Health applications

Gene therapy

Gene therapy [8] uses genetically modified viruses to deliver genes that can cure diseases in human cells.These viruses can deliver DNA or RNA genetic material to the targeted cells. Gene therapy is also used by inactivating mutated genes that are causing the disease using viruses. [9]

Viruses that have been used for gene therapy are, adenovirus, lentivirus, retrovirus and the herpes simplex virus. [10] The most common virus used for gene delivery come from adenoviruses as they can carry up to 7.5 kb of foreign DNA and infect a relatively broad range of host cells, although they have been known to elicit immune responses in the host and only provide short term expression. Other common vectors are adeno-associated viruses, which have lower toxicity and longer term expression, but can only carry about 4kb of DNA. [11] Herpes simplex viruses is a promising vector, have a carrying capacity of over 30kb and provide long term expression, although it is less efficient at gene delivery than other vectors. [12] The best vectors for long term integration of the gene into the host genome are retroviruses, but their propensity for random integration is problematic. Lentiviruses are a part of the same family as retroviruses with the advantage of infecting both dividing and non-dividing cells, whereas retroviruses only target dividing cells. Other viruses that have been used as vectors include alphaviruses, flaviviruses, measles viruses, rhabdoviruses, Newcastle disease virus, poxviruses, and picornaviruses. [11]

Although primarily still at trial stages, [13] it has had some successes. It has been used to treat inherited genetic disorders such as severe combined immunodeficiency [14] rising from adenosine deaminase deficiency (ADA-SCID), [15] although the development of leukemia in some ADA-SCID patients [11] along with the death of Jesse Gelsinger in another trial set back the development of this approach for many years. [16] In 2009 another breakthrough was achieved when an eight year old boy with Leber’s congenital amaurosis regained normal eyesight [16] and in 2016 GlaxoSmithKline gained approval to commercialise a gene therapy treatment for ADA-SCID. [15] As of 2018, there are a substantial number of clinical trials underway, including treatments for hemophilia, glioblastoma, chronic granulomatous disease, cystic fibrosis and various cancers. [11] Although some successes, gene therapy is still considered a risky technique and studies are still undergoing to ensure safety and effectiveness. [9]

Cancer treatment

Another potential use of genetically modified viruses is to alter them so they can directly treat diseases. This can be through expression of protective proteins or by directly targeting infected cells. In 2004, researchers reported that a genetically modified virus that exploits the selfish behaviour of cancer cells might offer an alternative way of killing tumours. [17] [18] Since then, several researchers have developed genetically modified oncolytic viruses that show promise as treatments for various types of cancer. [19] [20] [21] [22] [23]

Vaccines 

Most vaccines consist of viruses that have been attenuated, disabled, weakened or killed in some way so that their virulent properties are no longer effective. Genetic engineering could theoretically be used to create viruses with the virulent genes removed. In 2001, it was reported that genetically modified viruses can possibly be used to develop vaccines [24] against diseases such as, AIDS, herpes, dengue fever and viral hepatitis by using a proven safe vaccine virus, such as adenovirus, and modify its genome to have genes that code for immunogenic proteins that can spike the immune systems response to then be able to fight the virus. Genetic engineered viruses should not have reduced infectivity, invoke a natural immune response and there is no chance that they will regain their virulence function, which can occur with some other vaccines. As such they are generally considered safer and more efficient than conventional vaccines, although concerns remain over non-target infection, potential side effects and horizontal gene transfer to other viruses. [25] Another approach is to use vectors to create novel vaccines for diseases that have no vaccines available or the vaccines that are do not work effectively, such as AIDS, malaria, and tuberculosis. Vector-based vaccines have already been approved and many more are being developed. [26]

Heart pacemaker

In 2012, US researchers reported that they injected a genetically modified virus into the heart of pigs. This virus inserted into the heart muscles a gene called Tbx18 which enabled heartbeats. The researchers forecast that one day this technique could be used to restore the heartbeat in humans who would otherwise need electronic pacemakers. [27] [28]

Genetically modified viruses intended for use in the environment

Animals

In Spain and Portugal, by 2005 rabbits had declined by as much as 95% over 50 years due diseases such as myxomatosis, rabbit haemorrhagic disease and other causes. This in turn caused declines in predators like the Iberian lynx, a critically endangered species. [29] [30] In 2000 Spanish researchers investigated a genetically modified virus which might have protected rabbits in the wild against myxomatosis and rabbit haemorrhagic disease. [31] However, there was concern that such a virus might make its way into wild populations in areas such as Australia and create a population boom. [29] [4] Rabbits in Australia are considered to be such a pest that land owners are legally obliged to control them. [32]

Genetically modified viruses that make the target animals infertile through immunocontraception have been created [33] as well as others that target the developmental stage of the animal. [34] There are concerns over virus containment [33] and cross species infection. [35]

Trees

Since 2009 genetically modified viruses expressing spinach defensin proteins have been field trialed in Florida (USA). [36] The virus infection of orange trees aims to combat citrus greening disease, that had reduced orange production in Florida 70% since 2005. [37] A permit application has been pending since February 13, 2017 (USDA 17-044-101r) to extend the experimental use permit to an area of 513,500 acres, this would make it the largest permit of this kind ever issued by the USDA Biotechnology Regulatory Services.

Insect Allies program

In 2016 DARPA, an agency of the U.S. Department of Defense, announced a tender for contracts to develop genetically modified plant viruses for an approach involving their dispersion into the environment using insects. [38] [39] The work plan stated:

“Plant viruses hold significant promise as carriers of gene editing circuitry and are a natural partner for an insect-transmitted delivery platform.” [38]

The motivation provided for the program is to ensure food stability by protecting agricultural food supply and commodity crops:

"By leveraging the natural ability of insect vectors to deliver viruses with high host plant specificity, and combining this capability with advances in gene editing, rapid enhancement of mature plants in the field can be achieved over large areas and without the need for industrial infrastructure.” [38]

Despite its name, the “Insect Allies” program is to a large extent a viral program, developing viruses that would essentially perform gene editing of crops in already-planted fields. [40] [41] [42] [43] The genetically modified viruses described in the work plan and other public documents are of a class of genetically modified viruses subsequently termed HEGAAs (horizontal environmental gene alteration agents). The Insect Allies program is scheduled to run from 2017 to 2021 with contracts being executed by three consortia. There are no plans to release the genetically modified viruses into the environment, with testing of the full insect dispersed system occurring in greenhouses (Biosafety level 3 facilities have been mentioned). [44]

Concerns have been expressed about how this program and any data it generates will impact biological weapon control and agricultural coexistence, [45] [46] [47] though there has also been support for its stated objectives. [48]

Technological applications

Lithium-ion batteries

In 2009, MIT scientists created a genetically modified virus has been used to construct a more environmentally friendly lithium-ion battery. [49] [50] [51] The battery was constructed by genetically engineering different viruses such as, the E4 bacteriophage and the M13 bacteriophage, to be used as a cathode. This was done by editing the genes of the virus that code for the protein coat. The protein coat is edited to coat itself in iron phosphate to be able to adhere to highly conductive carbon-nanotubes. The viruses that have been modified to have a multifunctional protein coat can be used as a nano-structured cathode with causes ionic interactions with cations. Allowing the virus to be used as a small battery. Angela Blecher, the scientist who led the MIT research team on the project, says that the battery is powerful enough to be used as a rechargeable battery, power hybrid electric cars, and a number of personal electronics. [52] While both the E4 and M13 viruses can infect and replicate within their bacterial host, it unclear if they retain this capacity after being part of a battery.

Safety concerns and regulation

Bio-hazard research limitations

The National Institute of Health declared a research funding moratorium on select Gain-of-Function virus research in January 2015. [53] [54] In January 2017, the U.S. Government released final policy guidance for the review and oversight of research anticipated to create, transfer, or use enhanced potential pandemic pathogens (PPP). [55] Questions about a potential escape of a modified virus from a biosafety lab and the utility of dual-use-technology, dual use research of concern (DURC), prompted the NIH funding policy revision. [56] [57] [58]

GMO lentivirus incident

A scientist claims she was infected by a genetically modified virus while working for Pfizer. In her federal lawsuit she says she has been intermittently paralyzed by the Pfizer-designed virus. "McClain, of Deep River, suspects she was inadvertently exposed, through work by a former Pfizer colleague in 2002 or 2003, to an engineered form of the lentivirus, a virus similar to the one that can lead to acquired immune deficiency syndrome, or AIDS." [59] The court found that McClain failed to demonstrate that her illness was caused by exposure to the lentivirus, [60] but also that Pfizer violated whistleblower protection laws. [61]

Related Research Articles

<span class="mw-page-title-main">Genetically modified organism</span> Organisms whose genetic material has been altered using genetic engineering methods

A genetically modified organism (GMO) is any organism whose genetic material has been altered using genetic engineering techniques. The exact definition of a genetically modified organism and what constitutes genetic engineering varies, with the most common being an organism altered in a way that "does not occur naturally by mating and/or natural recombination". A wide variety of organisms have been genetically modified (GM), including animals, plants, and microorganisms.

<span class="mw-page-title-main">Gene therapy</span> Medical field

Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

<i>Indiana vesiculovirus</i> Species of virus

Indiana vesiculovirus, formerly Vesicular stomatitis Indiana virus is a virus in the family Rhabdoviridae; the well-known Rabies lyssavirus belongs to the same family. VSIV can infect insects, cattle, horses and pigs. It has particular importance to farmers in certain regions of the world where it infects cattle. This is because its clinical presentation is identical to the very important foot and mouth disease virus.

<i>Adenoviridae</i> Family of viruses

Adenoviruses are medium-sized, nonenveloped viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.

<span class="mw-page-title-main">Expression vector</span> Virus or plasmid designed for gene expression in cells

An expression vector, otherwise known as an expression construct, is usually a plasmid or virus designed for gene expression in cells. The vector is used to introduce a specific gene into a target cell, and can commandeer the cell's mechanism for protein synthesis to produce the protein encoded by the gene. Expression vectors are the basic tools in biotechnology for the production of proteins.

<span class="mw-page-title-main">Transduction (genetics)</span> Transfer process in genetics

Transduction is the process by which foreign DNA is introduced into a cell by a virus or viral vector. An example is the viral transfer of DNA from one bacterium to another and hence an example of horizontal gene transfer. Transduction does not require physical contact between the cell donating the DNA and the cell receiving the DNA, and it is DNase resistant. Transduction is a common tool used by molecular biologists to stably introduce a foreign gene into a host cell's genome.

SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that sometimes causes tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication and transcription.

<span class="mw-page-title-main">Human genetic enhancement</span> Technologies to genetically improve human bodies

Human genetic enhancement or human genetic engineering refers to human enhancement by means of a genetic modification. This could be done in order to cure diseases, prevent the possibility of getting a particular disease, to improve athlete performance in sporting events, or to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. These genetic enhancements may or may not be done in such a way that the change is heritable.

Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches use three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout uses RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.

<i>Gammaretrovirus</i> Genus of viruses

Gammaretrovirus is a genus in the Retroviridae 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 birds.

The murine leukemia viruses 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 positive sense, single-stranded RNA (ssRNA) genome that replicates through a DNA intermediate via the process of reverse transcription.

<span class="mw-page-title-main">Viral vector</span> Biotechnology to deliver genetic material into a cell

Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture. Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect. Delivery of genes or other genetic material by a vector is termed transduction and the infected cells are described as transduced. Molecular biologists first harnessed this machinery in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage λ to infect monkey kidney cell maintained in culture.

<span class="mw-page-title-main">Gene delivery</span> Introduction of foreign genetic material into host cells

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 delivery to remain stable within the host cell and can either integrate into the genome or replicate independently of it. This requires foreign DNA to be synthesized as part of a vector, which is designed to enter the desired host cell and deliver the transgene to that cell's genome. Vectors utilized as the method for gene delivery can be divided into two categories, recombinant viruses and synthetic vectors.

<span class="mw-page-title-main">Virus</span> Infectious agent that replicates in cells

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. Viruses are found in almost every ecosystem on Earth and are the most numerous type of biological entity. Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants and the discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898, more than 11,000 of the millions of virus species have been described in detail. The study of viruses is known as virology, a subspeciality of microbiology.

<span class="mw-page-title-main">Vectors in gene therapy</span>

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses and those that use naked DNA or DNA complexes.

<span class="mw-page-title-main">Lentiviral vector in gene therapy</span>

Lentiviral vectors in gene therapy is a method by which genes can be inserted, modified, or deleted in organisms using lentiviruses.

Synthetic virology is a branch of virology engaged in the study and engineering of synthetic man-made viruses. It is a multidisciplinary research field at the intersection of virology, synthetic biology, computational biology, and DNA nanotechnology, from which it borrows and integrates its concepts and methodologies. There is a wide range of applications for synthetic viral technology such as medical treatments, investigative tools, and reviving organisms.

Horizontal Environmental Genetic Alteration Agents (HEGAAs) are any artificially developed agents that are engineered to edit the genome of eukaryotic species they infect when intentionally dispersed into the environment (outside of contained facilities such as laboratories or hospitals).

mRNA vaccine Type of vaccine

An mRNAvaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into immune cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.

<span class="mw-page-title-main">Viral vector vaccine</span> Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.

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