Cancer-Causing Viruses
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
RNA tumor viruses are retroviruses. A retrovirus is an RNA virus that replicates in a host cell through the process of reverse transcription. First, it uses its own reverse transcriptase enzyme to produce DNA from its RNA genome—the reverse of the usual pattern, thus, retro (backward). This new DNA is then incorporated into the host’s genome by an enzyme called integrase. The cell then treats the viral DNA as part of its own instructions, making the proteins required to assemble new copies of the virus (Figure 1.1). Retroviruses are enveloped viruses that belong to the viral family of Retroviridae. The incorporation of the viral DNA into the host’s genome converts proto-oncogenes—the cellular genes that code for components of the cellular machinery that regulates cell proliferation, differentiation, and death—into oncogenes in two ways: the gene sequence may be altered or truncated so that it codes for proteins with abnormal activity, or the gene may be brought under the control of powerful viral regulators that cause its product to be made in excess or in inappropriate circumstances. Retroviruses may also exert similar oncogenic effects by insertional mutation when DNA copies of the viral RNA are integrated into the host-cell genome at a site close to or even within proto-oncogenes. Cellular oncogenes are expressed by the cell at some period in the life of the cell, often when the cell is growing, replicating, and differentiating normally. They are usually proteins that are involved in growth control. Cellular oncogenes are highly conserved.
What is HIV?
Omar Bagasra, Donald Gene Pace in A Guide to AIDS, 2017
Human immunodeficiency virus (HIV) belongs to a group of retroviruses called lentiviruses [2]. Lentiviruses are more evolved versions of retroviruses that infect primates, including humans. The genetic structure of retroviruses is composed of two identical copies of ribonucleic acid (RNA). The presence of two identical copies, or pairs, is unique to retroviruses because all other viruses contain only one copy of their genomes. Therefore, retroviruses have two single copies of RNA. HIV is a retrovirus and, like all other viruses, it requires a live, functioning host cell. The most unique aspect of retroviruses is that they are capable of converting their single stranded RNA into deoxyribonucleic acid (DNA). For this process, they use an enzyme called reverse transcriptase (RT). Before the discovery of retroviruses, this RT process was considered impossible, and the basic dogma was that DNA transcribed into RNA, but never the other way around, and then RNA translates into proteins. HIVs are of two basic kinds: HIV-1 and HIV-2. The latter is not a major pathogen for humans; it essentially has a narrow geographic range and is found in West Africa. In this book, whenever we use HIV, we will be talking about HIV-1.
Acute and Chronic Transforming Retroviruses
Pimentel Enrique in Oncogenes, 2020
Chronic retroviruses replicate through a double-stranded DNA intermediate, the provirus, which is integrated into the genome of the host cell. The provirus genome sequences are complementary to the RNA sequences of the respective virus, with the exception that there are LTRs at both ends of the provirus. The LTRs are stretches of linear double-stranded DNA with terminally redundant sequences 300 to 1200 bp in length. They are synthesized from the viral RNA genome by reverse transcriptase present in virions and are formed by duplication of the nonstructural segments of the retrovirus genome, containing the sequences 5′-U3-r-U5-3′ (Figure 1). The detailed structure and nucleotide sequences of LTRs and adjacent genomic regions from 19 different type-C and type-B retroviruses have been determined and compared.137
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.
Xenotransplantation
Published in Organogenesis, 2018
Srijan Tandukar, Sundaram Hariharan
Despite the encouraging results with recent experiments on pigs showing the inactivation of multiple genes encoding for PERVs, there is still a theoretical chance that a retrovirus may be transmitted to the recipient either due to imperfections in the technique that need to be refined further, or due to the limits of our current knowledge regarding the way these genes behave and get transmitted. Should solid organ xenotransplantation come to reality in the future, inevitable comparisons will be made to human allografts and these studies on outcomes are going to be vital in delineating criteria for allo- versus xeno-transplantation for future recipients. The societal acceptance (including possible conflicts with religious beliefs and animal rights groups) to the idea of harvesting organs from another species for transplant in humans is something the transplant community will need to address on an ongoing basis.2 Porcine heart valves, encapsulated pig islet cell transplantation, pig corneal transplantation and bovine vessels have already been used successfully in humans which has had good acceptance in the society in general and solid organ xenotransplantation should be presented to the community in a similar fashion.2
Gene therapy for alpha-1 antitrypsin deficiency: an update
Published in Expert Opinion on Biological Therapy, 2023
Debora Pires Ferreira, Alisha M Gruntman, Terence R Flotte
Successive studies using retroviruses and adenoviruses were performed in larger animal models, such as rabbits and dogs, showed transient hAAT expression and/or treatment-related side effects due to high immunogenicity, along with presenting a potential risk of insertional mutagenesis and further cytotoxicity [27–30]. The disadvantages of these delivery systems have discouraged their use in human trials. To overcome these, current studies are focusing mostly on recombinant adeno-associated virus (rAAV) as a vector for gene delivery. As a vector for gene therapy, rAAVs have the advantages of being non-pathogenic to humans, induce low immunogenicity, are able transfect dividing and non-dividing cells, do not integrate into the genome of the target cells, and are able to produce prolonged expression of the transgene (in non-dividing cells), making them promising candidates for safe and efficient AAT gene therapy [31]. Furthermore, AAVs have many capsid variations, which affects their affinities for extracellular receptors on many different cell and tissue types, allowing for a range of therapeutic targets [32,33]. This is advantageous because there is concern that viral vector delivery to the liver could exacerbate the liver disease, which currently only develops in 5–10% of AATD patients and could be triggered or accelerated by environmental factors [19,34].