Lentiviral vector in gene therapy

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

Contents

Lentiviruses are a family of viruses that are responsible for diseases like AIDS, which infect by inserting DNA into their host cells' genome. [1] Many such viruses have been the basis of research using viruses in gene therapy, but the lentivirus is unique in its ability to infect non-dividing cells, and therefore has a wider range of potential applications. [2] Lentiviruses can become endogenous (ERV), integrating their genome into the host germline genome, so that the virus is henceforth inherited by the host's descendants. Scientists use the lentivirus' mechanisms of infection to achieve a desired outcome to gene therapy. Lentiviral vectors in gene therapy have been pioneered by Luigi Naldini. [3] [4]

Structure of a virion of HIV, a type of lentivirus. A membrane with protruding glycoproteins surrounds a capsid containing enzymes and the viral RNA genome. HI-virion-structure en.svg
Structure of a virion of HIV, a type of lentivirus. A membrane with protruding glycoproteins surrounds a capsid containing enzymes and the viral RNA genome.

To understand the capabilities of a lentiviral vector, one has to consider the biology of the infection process.[ editorializing ] The lentivirus is a retrovirus, meaning it has a single stranded RNA genome with a reverse transcriptase enzyme. Lentiviruses also have a viral envelope with protruding glycoproteins that aid in attachment to the host cell's outer membrane. The virus contains a reverse transcriptase molecule found to perform transcription of the viral genetic material upon entering the cell. Within the viral genome are RNA sequences that code for specific proteins that facilitate the incorporation of the viral sequences into the host cell genome. The "gag" gene codes for the structural components of the viral nucleocapsid proteins: the matrix (MA/p17), the capsid (CA/p24) and the nucleocapsid (NC/p7) proteins. The "pol" domain codes for the reverse transcriptase and integrase enzymes. Lastly, the "env" domain of the viral genome encodes for the glycoproteins and envelope on the surface of the virus.[1][ full citation needed ]

There are multiple steps involved in the infection and replication of a lentivirus in a host cell. In the first step the virus uses its surface glycoproteins for attachment to the outer surface of a cell. More specifically, lentiviruses attach to the CD4 glycoproteins on the surface of a host's target cell. The viral material is then injected into the host cell's cytoplasm. Within the cytoplasm, the viral reverse transcriptase enzyme performs reverse transcription of the viral RNA genome to create a viral DNA genome. The viral DNA is then sent into the nucleus of the host cell where it is incorporated into the host cell's genome with the help of the viral enzyme integrase. From now on, the host cell starts to transcribe the entire viral RNA and express the structural viral proteins, in particular those that form the viral capsid and the envelope. The lentiviral RNA and the viral proteins then assemble and the newly formed virions leave the host cell when enough are made.[ citation needed ]

Two methods of gene therapy using lentiviruses have been proposed. In the ex vivo methodology, cells are extracted from a patient and then cultured. A lentiviral vector carrying therapeutic transgenes are then introduced to the culture to infect them. The now modified cells continue to be cultured until they can be infused into the patient. In vivo gene therapy is the sample injection of viral vectors containing transgenes into the patient. [5]

Designing a lentivirus vector

Lentiviruses are modified to act as a vector to insert beneficial genes into cells. Unlike other retroviruses, which cannot penetrate the nuclear envelope and can therefore only act on cells while they are undergoing mitosis, lentiviruses can infect cells whether or not they are dividing (shown to be largely due to the capsid protein). [6] Many cell types, like neurons, do not divide in adult organisms, so lentiviral gene therapy is a good candidate for treating conditions that affect those cell types. [7]

Some experimental applications of lentiviral vectors [8] have been done in gene therapy in order to cure diseases like Diabetes mellitus, Murine haemophilia A, prostate cancer, chronic granulomatous disease, and vascular diseases.[ citation needed ]

HIV-derived lentiviral vectors have been widely developed for their ability to target specific genes through the coactivator PSIP1. [9] This target specificity allows for the development of lentiviral gene vectors that do not carry the risk of randomly inserting themselves into normally functioning genes. As HIV is pathogenic, it must be genetically modified to remove its disease-causing properties and its ability to replicate itself. This can be achieved by deleting viral genes that are unnecessary for transduction of therapeutic transgenes. It has been proposed that by targeting the "gag" and "env" domains, enough of the HIV-1 genome can be deleted without losing its effectiveness in gene therapy while minimizing viral genes integrated into the patient. [10] Genes may also be replaced rather than disrupted as another method to reduce the risks associated with the use of HIV-1. [7]

Other lentiviruses such as Feline immunodeficiency virus [11] and Equine infectious anemia virus [12] have been developed for use in gene therapy and are of interest due to the inability to cause serious disease in human hosts. Equine infectious anemia virus in particular has been shown to perform somewhat better than HIV-1 in hematopoietic stem cells [13]

Insertional mutagenesis

Historically, lentiviral vectors included strong viral promoters which had a side effect of insertional mutagenesis, nuclear DNA mutations that affect the function of a gene. [14] These strong viral promotors were shown to be the main cause of cancer formation. [14] As a result, viral promotors have been replaced by cellular promotors and regulatory sequences. [14]

Contrast with other viral vectors

As mentioned, lentiviruses have the unique ability to infect non-dividing cells. Beyond that, there are several other properties that distinguish lentiviral vectors from other viral vectors. Such properties are important to consider when determining whether lentiviruses are appropriate for a given treatment.

Gammaretroviruses

Gammaretroviruses are retroviruses like lentiviruses. Murine leukemia viruses (MLVs) were among the first to be investigated for their use in gene therapy. However, recent research has favored lentiviruses for their ability to integrate into non-dividing cells. More practically, gammaretroviruses have an affinity for integrating themselves near oncogene promoters, bringing forward an adverse risk of tumors. [15] MLVs may be replication competent, meaning they can replicate in the host cell. These replication-competent viruses offer stable gene transfer and tumor and tissue specific targeting. [16]

Adenoviruses

In gene therapy, adenoviruses differ from lentiviruses in many ways, some of which provide advantages over lentiviruses. Transduction efficiency is higher in adenoviruses compared to lentiviruses. [5] Secondly, most human cells have receptors for adenoviruses [17] likely as a result of the wide variety of adenovirus diseases in humans. However, this presents a drawback[ editorializing ] - as adenoviruses frequently infect humans, this builds an immune response in the body. Such a response can reduce the efficiency of adenoviral vector therapies and can result in adverse reactions such as inflammation of tissues. [18] Research has been conducted to exploit this immune response to target cancerous cells and to develop vaccines. [19] Hybrid adenovirus-retroviruses (specifically MLVs) have also been developed to exploit the benefits of MLVs and adenoviruses. [20]

Applications

Severe combined immunodeficiency disease

The ADA deficient variant of severe combined immunodeficiency (SCID) was treated highly successfully in a multi-year study reported in 2021. Over 95% of treated patients continued to be event free after 36 months, and 100% of patients survived this normally lethal disease. A self-inactivating lentiviral vector, EFS-ADA LV, was used to insert a functional ADA gene in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). [21]

Vascular transplants

In a study designed to enhance the outcomes of vascular transplant through vascular endothelial cell gene therapy, the third generation of Lentivirus showed to be effective in the delivery of genes to moderate venous grafts and transplants in procedures like coronary artery bypass. Because the virus has been adapted to lose most of its genome, the virus becomes safer and more effective in transplanting the required genes into the host cell. A drawback to this therapy is explained in the study that long-term gene expression may require the use of promoters and can aid in a greater trans-gene expression. The researchers accomplished this by the addition of self-inactivating plasmids and creating a more universal tropism by pseudotyping a vesicular stomatitis virus glycoprotein. [22]

Chronic granulomatous disease

In chronic granulomatous disease (CGD), immune functioning is deficient as a result of the mutations in components of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) enzyme in phagocyte cells, which catalyzes the production of superoxide free radicals. If this enzyme becomes deficient, the phagocytes can't kill effectively the engulfed bacteria, so granulomas can be formed. Study performed in mice emphasizes the use of lineage-specific lentiviral vectors to express a normal version of one of the mutant CGD proteins, allowing white blood cells to now make a functional version of the NADPH oxidase. Scientists developed this strain of lentivirus by transinfecting 293T cells with pseudotyped virus with the vesicular stomatitis G protein. The viral vector's responsibility was to increase the production of a functional NADPH oxidase gene in these phagocytic cells. They did this to create an affinity for myeloid cells. [23]

Prostate cancer

With prostate cancer, the lentivirus is transformed by being bound to trastuzumab to attach to androgen-sensitive LNCaP and castration-resistant C4-2 human prostate cancer cell lines. These two cells are primarily responsible for secretion of excess human epidermal growth factor receptor 2 (HER-2), which is a hormone linked to prostate cancer. By attaching to these cells and changing their genomes, the lentivirus can slow down, and even kill, the cancer-causing cells. Researchers caused the specificity of the vector by manipulating the Fab region of the viral genome and pseudotyped it with the Sindbis virus. [24]

Haemophilia A

Haemophilia A has also been studied in gene therapy with a lentiviral vector in mice. The vector targets the haematopoietic cells in order to increase the amount of factor VIII, which is affected in haemophilia A. But this continues to be a subject of study as the lentivirus vector was not completely successful in achieving this goal. They did this by trans-infecting the virus in a 293T cell, creating a virus known as 2bF8 expressing generation of viral vectors. [25]

Rheumatoid arthritis

Studies have also found that injection of a lentiviral vector with IL-10 expressing genes in utero in mice can suppress, and prevent, rheumatoid arthritis and create new cells with constant gene expression. This contributes to the data on stem cells and in utero inoculation of viral vectors for gene therapy. The target for the viral vector in this study, were the synovial cells. Normally functioning synovial cells produce TNFα and IL-1. [26]

Diabetes mellitus

Like many of the in utero studies, the lentiviral vector gene therapy for diabetes mellitus is more effective in utero as the stem cells that become affected by the gene therapy create new cells with the new gene created by the actual viral intervention. The vector targets the cells within the pancreas to add insulin secreting genes to help control diabetes mellitus. Vectors were cloned using a cytomegalovirus promoter and then co-transinfected in the 293T cell. [27]

Neurological disease

As mature neurons do not divide, lentiviruses are ideal for division independent gene therapy. Studies of lentiviral gene therapy have been conducted on patients with advanced Parkinson's disease [28] and aging-related atrophy of neurons in primates. [29]

See also

Related Research Articles

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

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

<span class="mw-page-title-main">Retrovirus</span> Family of viruses

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. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The 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, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.

<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.

<i>Feline immunodeficiency virus</i> Species of virus

Feline immunodeficiency virus (FIV) is a Lentivirus that affects cats worldwide, with 2.5% to 4.4% of felines being infected.

<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.

<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).

Lentivirus is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lentiviruses are distributed worldwide, and are known to be hosted in apes, cows, goats, horses, cats, and sheep as well as several other mammals.

<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.

<span class="mw-page-title-main">Short hairpin RNA</span> Type of RNA

A short hairpin RNA or small hairpin RNA is an artificial RNA molecule with a tight hairpin turn that can be used to silence target gene expression via RNA interference (RNAi). Expression of shRNA in cells is typically accomplished by delivery of plasmids or through viral or bacterial vectors. shRNA is an advantageous mediator of RNAi in that it has a relatively low rate of degradation and turnover. However, it requires use of an expression vector, which has the potential to cause side effects in medicinal applications.

<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.

Visna-maedi virus from the genus Lentivirus and subfamily Orthoretrovirinae, is a retrovirus that causes encephalitis and chronic pneumonitis in sheep. It is known as visna when found in the brain, and maedi when infecting the lungs. Lifelong, persistent infections in sheep occur in the lungs, lymph nodes, spleen, joints, central nervous system, and mammary glands; The condition is sometimes known as ovine progressive pneumonia (OPP), particularly in the United States, or Montana sheep disease. White blood cells of the monocyte/macrophage lineage are the main target of the virus.

Gene therapy using lentiviral vectors was being explored in early stage trials as of 2009.

Bovine immunodeficiency virus (BIV) is a retrovirus belonging to the genus Lentivirus. It is similar to the human immunodeficiency virus (HIV) and infects cattle. The cells primarily infected are lymphocytes and monocytes/macrophages.

<span class="mw-page-title-main">Genetically modified virus</span> Species of virus

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.

<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).

Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus.

Equine foamy virus (EFV), also called foamy virus (FV), is virus in the genus Equispumavirus. It shares similarities, with respect to replication, with lentiviruses. EFV, along with other FVs are from the family Retroviridae and subfamily Spumaretrovirinae. Spumarivuses, such as EFV, are complicated retroviruses that have been characterized in many animals including nonhuman primates, cattle, cats. Additionally, these viruses have been identified in animals that most often carry lentiviruses.

Pierre Charneau is a French virologist, inventor, and head of the Molecular Virology and Vaccinology Unit (VMV) at the Pasteur Institute and an acknowledged specialist in HIV, lentiviral gene transfer vectors, and their medical applications. His discovery of the central DNA-flap structure in the HIV genome, and its role in viral entry into the nucleus of the infected cell, grounded the optimization of lentiviral vectors and allowed for more than 20 years of development in gene therapy and vaccines based on this gene delivery technology. Charneau has published more than 100 research articles and holds 25 patents in the field of HIV and lentiviral vectors.

<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.

References

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