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The Viruses
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The replication process in the RNA tumor viruses is unique. The single-stranded viral RNA template is used to produce an initial DNA-RNA hybrid, which is then converted by DNA polymerase into a double stranded DNA linear intermediate. The DNA intermediate integrates into the host cell DNA and is referred to as a “provirus.” The provirus is transcribed into both viral messenger and viral genomic RNA. The RNA viruses containing reverse transcriptase were named the Retroviridae (Table 16.1) in recognition of the retrograde flow of genetic information from RNA into DNA. Retroviruses are known to infect a wide variety of animals, including humans, and are associated with certain types of cancer. They may also induce immunosuppressive or immune-mediated diseases, or may exist as stable members of the host germ line.
Challenges in Delivering Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
Retroviruses are a subsection of viruses, which can place a copy of its own single stranded RNA makeup into the DNA of the virion’s host cell. These viruses can retro transcribe their single-stranded RNA by retro-transcribing it into linear double-stranded DNA, which causes a seamless insertion of the virus and its contents with little immunological repercussions, if any. An advantage of retroviral vectors in gene therapy is the ability to retro-transcribe their RNA into DNA, which when integrated into the host cell’s DNA, is a permanent modification [7]. With this permeant modification, it leads to an effective way to maintain self-renewing genetic material. However, the integrated DNA does not warrant stable expression of those transduced genes. In situations where a permeant outcome is the most feasible option, a retroviral vector could be coupled with targeted gene therapy for a possible treatment option.
Aids and Hepatitis
Published in T.M. Craft, P.M. Upton, Key Topics In Anaesthesia, 2021
Acquired immunodeficiency syndrome (AIDS) was first reported in 1981. An exponential increase in the numbers of seropositive people infected with human immunodeficiency virus (HIV) has been seen world-wide with 30 million thought to be infected by 1998. The virus, a retrovirus, is transmitted through sexual contact, perinatally, and via blood and blood products. It is becoming more common in the heterosexual population and in children. Infection preferentially affects T helper lymphocytes resulting in immunosuppression and the eventual development of ‘AIDS’ in most people infected with the virus. The appearance of symptomatic immunosuppression takes a variable length of time. Opportunistic infections, malignancies (Kaposi’s sarcoma, non-Hodgkin’s lymphoma) and neurological manifestations occur.
Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer
Published in Expert Opinion on Biological Therapy, 2021
Sara A. Collins, Ashish H. Shah, Derek Ostertag, Noriyuki Kasahara, Douglas J. Jolly
Physical barriers to virus replication: Diffusely infiltrating glioma cells may be difficult to reach for virus released from infected cells in the body of the tumor, as intervening quiescent normal brain tissue represents a physical barrier to infecting these cells. Similarly, necrotic areas of the tumor also represent a physical barrier for virus particles, which must traverse these areas by simple diffusion before they can reach a cancer cell substrate for further infection and replication. However, as retroviruses permanently integrate into the cancer cell genome, infected cancer cells as well as their progeny cells constitutively produce virus. As long as these cells also infiltratively migrate alongside uninfected cells, they can transmit the virus through direct cell-cell contact whenever the uninfected cells enter mitosis.
Merits of the ‘good’ viruses: the potential of virus-based therapeutics
Published in Expert Opinion on Biological Therapy, 2021
Qianyu Zhang, Wen Wu, Jinqiang Zhang, Xuefeng Xia
Nowadays, adenovirus, retrovirus, lentivirus, and adeno-associated virus (AAV) constitute over half of the vectors used in gene therapy (Source: Wiley Gene Therapy Clinical Trials Worldwide, http://www.abedia.com/wiley.) γ-retrovirus MLV (murine leukemia virus) was among the first viruses tested in human trials, which was intended for the therapy of ADA-SCID and X-SCID as mentioned above. Retroviruses possess high efficiency in the transduction of replicating cells, integration into host cell genome, and low incidence of immunogenicity, making the therapeutic gene expression permanent [56]. Owing to the fact that it might promote host proto-oncogene activation, much attention has been focused on addressing the insertional mutagenesis by the vectors. Techniques such as deleting the enhancer or promoter of the long terminal repeat (LTR) to develop self-inactivating (SIN) vectors have been developed [57]. Lentiviral vectors were subsequently developed which can transfer genes into nondividing cells. They allowed for a significant extension of the range of cell lines of therapeutic benefit. In 1996, the human immunodeficiency virus (HIV) was the first to be engineered into a lentiviral vector for both mitotic and nondividing cells [58]. Later, SIN lentiviral vectors have also been established to improve safety. Lentiviral vectors such as HIV tend to integrate in downstream regions within transcribed genes, which are significantly safer regions compared with promoter elements [59]. This could be translated toward improved clinical safety.
Nanotechnology-enabled gene delivery for cancer and other genetic diseases
Published in Expert Opinion on Drug Delivery, 2023
Tong Jiang, Karina Marie Gonzalez, Leyla Estrella Cordova, Jianqin Lu
Viral delivery systems utilize the natural characteristics that viruses can introduce their own genetic material into host cells, where the target genome is integrated with virus genes. Viral vectors include retroviruses, lentiviruses, adenoviruses and adeno-associated viruses, etc. Cells can be transfected efficiently because of the ability of utilizing the innate infectivity of wild-type viruses [30] to achieve a therapeutic effect. Most retroviruses are active only in dividing cells [31] and one of the features of retroviruses is that they can be incorporated into the cell genome, allowing stable expression of therapeutic genes [31] This prolonged-term expression can provide effective therapeutic effects while reducing the immune response to the host [32]. Lentivirus are a type of retrovirus that can infect both dividing and quiescent cells [33]. Compared with alternative viral vectors, lentiviruses have a larger capacity to carry additional complex genome, which can be integrated into host genome to achieve a stable long-term expression. The structural and biological properties of adenoviruses and adeno-associated viruses make them the most commonly used as a vector for gene therapy in current clinical trials [34]. AAV-based gene therapy agent Glybera, for example, has been indicated for adult patients with familial lipoprotein lipase deficiency treatment. Some progress has been made of viral vectors gene delivery, which is used in most cell and gene therapy projects. Nonetheless, there are still many limitations, such as carcinogenic effect, potential immunogenicity, poor specificity, difficulty in size adjust of virus, and complex preparation process with a high cost [35].