Helper dependent virus

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A helper dependent virus, also termed a gutless virus, is a synthetic viral vector dependent on the assistance of a helper virus in order to replicate, [1] and can be used for purposes such as gene therapy. Naturally-occurring satellite viruses are also helper virus dependent, and can sometimes be modified to become viral vectors.

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Viral vector

Since the genome of the gutless virus does not include genes encoding the enzymes and/or structural proteins required to replicate, it is deemed safe for use in gene therapy since an infection cannot occur except in the presence of a suitable helper virus. [2]

Well established protocols allow scientists to propagate helper dependent viruses in the lab. However, using an actual helper virus poses problems when it comes to purification of a desired transgenic virus. Therefore, lab methods often utilize minimal fragments of the helper DNA that can serve this purpose without creating unwanted virus. This process usually involves the introduction of three separate DNA plasmids into a eukaryotic cell line through a process called transfection. These plasmids contain either transgenic DNA or replication and capsid encoding DNA, plus helper DNA. Every cell that is successfully transfected with all three DNA fragments will produce the necessary proteins to produce infective viruses. These viruses will only have transgenic DNA encapsidated and therefore once they've infected a patient's cell, they will not be capable of reproducing. [3]

Satellite virus

Helper dependent viruses can also occur in nature without being "gutted". The term satellite virus has been given to a large group of viruses that all require the presence of another virus to replicate. Many of these are plant viruses, [4] but animal viruses can be seen in the case of dependoviruses.

Within the family parvoviridae, the dependovirus genus was given a distinct classification due to their dependence on another virus. The most widely known dependovirus is adeno-associated virus (AAV) which was originally discovered as a contaminant in a sample of simian adenovirus. [5] Though AAV is considered to be dependent on adenovirus, it is able to replicate in the presence of herpesvirus as well as certain cytotoxic events such as UV irradiation or some carcinogens [6] During the course of a natural dependovirus infection, if the helper virus is not present, the dependovirus is often capable of integrating into the host genome and going into a latent phase of its life cycle—effectively waiting for the next helper virus infection. [6] For gene therapy uses, the vector is stripped of its ability to integrate. Because AAV can deliver transgenic material in a non-replicating form, it is a strong candidate for gene therapy and is currently used in about 8% of clinical trials. [7]

Hepatitis D virus (HDV) is an example of a replication defective, helper dependent ssRNA virus because it requires Hepatitis B virus (HBV) to provide HBV surface antigen (HBsAg) for the encapsidation of its genome. The envelope proteins on the outer surface of HDV are entirely provided by HBV.

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An episome is a special type of plasmid, which remains as a part of the eukaryotic genome without integration. Episomes manage this by replicating together with the rest of the genome and subsequently associating with metaphase chromosomes during mitosis. Episomes do not degrade, unlike standard plasmids, and can be designed so that they are not epigenetically silenced inside the eukaryotic cell nucleus. Episomes can be observed in nature in certain types of long-term infection by adeno-associated virus or Epstein-Barr virus. In 2004, it was proposed that non-viral episomes might be used in genetic therapy for long-term change in gene expression.

<i>Parvoviridae</i> Family of viruses

Parvoviruses are a family of animal viruses that constitute the family Parvoviridae. They have linear, single-stranded DNA (ssDNA) genomes that typically contain two genes encoding for a replication initiator protein, called NS1, and the protein the viral capsid is made of. The coding portion of the genome is flanked by telomeres at each end that form into hairpin loops that are important during replication. Parvovirus virions are small compared to most viruses, at 23–28 nanometers in diameter, and contain the genome enclosed in an icosahedral capsid that has a rugged surface.

Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus (HDV). HDV is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a satellite because it can propagate only in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).

<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.

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">Satellite (biology)</span> Subviral agent which depends on a helper virus for its replication

A satellite is a subviral agent that depends on the coinfection of a host cell with a helper virus for its replication. Satellites can be divided into two major classes: satellite viruses and satellite nucleic acids. Satellite viruses, which are most commonly associated with plants, are also found in mammals, arthropods, and bacteria. They encode structural proteins to enclose their genetic material, which are therefore distinct from the structural proteins of their helper viruses. Satellite nucleic acids, in contrast, do not encode their own structural proteins, but instead are encapsulated by proteins encoded by their helper viruses. The genomes of satellites range upward from 359 nucleotides in length for satellite tobacco ringspot virus RNA (STobRV).

<span class="mw-page-title-main">Adeno-associated virus</span> Species of virus

Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus Dependoparvovirus, which in turn belongs to the family Parvoviridae. They are small replication-defective, nonenveloped viruses and have linear single-stranded DNA (ssDNA) genome of approximately 4.8 kilobases (kb).

<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 cells 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.

<i>Dependoparvovirus</i> Genus of viruses

Dependoparvovirus is a genus in the subfamily Parvovirinae of the virus family Parvoviridae; they are Group II viruses according to the Baltimore classification. Some dependoparvoviruses are also known as adeno-associated viruses because they cannot replicate productively in their host cell without the cell being coinfected by a helper virus such as an adenovirus, a herpesvirus, or a vaccinia virus.

<span class="mw-page-title-main">HBx</span>

HBx is a hepatitis B viral protein. It is 154 amino acids long and interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host. It forms a heterodimeric complex with its cellular target protein, and this interaction dysregulates centrosome dynamics and mitotic spindle formation. It interacts with DDB1 redirecting the ubiquitin ligase activity of the CUL4-DDB1 E3 complexes, which are intimately involved in the intracellular regulation of DNA replication and repair, transcription and signal transduction.

<i>Hepatitis B virus</i> Species of the genus Orthohepadnavirus

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.

The transmission of hepadnaviruses between their natural hosts, humans, non-human primates, and birds, including intra-species host transmission and cross-species transmission, is a topic of study in virology.

<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.

Self-complementary adeno-associated virus (scAAV) is a viral vector engineered from the naturally occurring adeno-associated virus (AAV) to be used as a tool for gene therapy. Use of recombinant AAV (rAAV) has been successful in clinical trials addressing a variety of diseases. This lab-made progeny of rAAV is termed "self-complementary" because the coding region has been designed to form an intra-molecular double-stranded DNA template. A rate-limiting step for the standard AAV genome involves the second-strand synthesis since the typical AAV genome is a single-stranded DNA template. However, this is not the case for scAAV genomes. Upon infection, rather than waiting for cell mediated synthesis of the second strand, the two complementary halves of scAAV will associate to form one double stranded DNA (dsDNA) unit that is ready for immediate replication and transcription. The caveat of this construct is that instead of the full coding capacity found in rAAV (4.7–6kb) scAAV can only hold about half of that amount (≈2.4kb).

Saswati Chatterjee is a virologist working as a professor at the Los Angeles City of Hope National Medical Center in the research department. Some of the viral areas she researches are: stem cells, gene therapy, genome editing, and parvovirus. Her main and current area of research is using Adeno-Associated Virus Vectors (AAV-Vectors). Additionally, she has had a role in many publications.

Transient expression, more frequently referred to "transient gene expression", is the temporary expression of genes that are expressed for a short time after nucleic acid, most frequently plasmid DNA encoding an expression cassette, has been introduced into eukaryotic cells with a chemical delivery agent like calcium phosphate (CaPi) or polyethyleneimine (PEI). However, unlike "stable expression," the foreign DNA does not fuse with the host cell DNA, resulting in the inevitable loss of the vector after several cell replication cycles. The majority of transient gene expressions are done with cultivated animal cells. The technique is also used in plant cells; however, the transfer of nucleic acids into these cells requires different methods than those with animal cells. In both plants and animals, transient expression should result in a time-limited use of transferred nucleic acids, since any long-term expression would be called "stable expression."

Adeno-associated virus (AAV) has been researched as a viral vector in gene therapy for cancer treatment as an Oncolytic Virus. Currently there are not any FDA approved AAV cancer treatments, as the first FDA approved AAV treatment was approved December 2017. However, there are many Oncolytic AAV applications that are in development and have been researched.

<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.

<span class="mw-page-title-main">Intracellular delivery</span> Scientific research area

Intracellular delivery is the process of introducing external materials into living cells. Materials that are delivered into cells include nucleic acids, proteins, peptides, impermeable small molecules, synthetic nanomaterials, organelles, and micron-scale tracers, devices and objects. Such molecules and materials can be used to investigate cellular behavior, engineer cell operations or correct a pathological function.

References

  1. ↑ Alba, R; Bosch, A; Chillon, M (2005). "Gutless adenovirus: Last-generation adenovirus for gene therapy". Gene Therapy. 12: S18–27. doi:10.1038/sj.gt.3302612. PMID   16231052.
  2. ↑ Gonçalves, Manuel AFV (2005). "Adeno-associated virus: From defective virus to effective vector". Virology Journal. 2: 43. doi: 10.1186/1743-422X-2-43 . PMC   1131931 . PMID   15877812.
  3. ↑ Xiao, X; Li, J; Samulski, RJ (1998). "Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus". Journal of Virology. 72 (3): 2224–32. doi:10.1128/JVI.72.3.2224-2232.1998. PMC   109519 . PMID   9499080.
  4. ↑ Knipe, David M.; Howley, Peter M. (2007). Fields Virology (5th ed.). Lippincott Williams & Wilkins. pp. 126–7.
  5. ↑ Atchison, R. W.; Casto, B. C.; Hammon, W. McD. (1965). "Adenovirus-Associated Defective Virus Particles". Science. 149 (3685): 754–6. Bibcode:1965Sci...149..754A. doi:10.1126/science.149.3685.754. PMID   14325163.
  6. 1 2 Berns, KI (1990). "Parvovirus replication". Microbiological Reviews. 54 (3): 316–29. doi:10.1128/MMBR.54.3.316-329.1990. PMC   372780 . PMID   2215424.
  7. ↑ "Vectors Used in Gene Therapy Clinical Trials". Gene Therapy Clinical Trials Worldwide. September 2019. Retrieved 14 March 2020.


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