The Viruses
Julius P. Kreier in 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.
The Acquired Immunodeficiency Syndrome (AIDS)
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
After penetration and uncoating, the viral genome is converted from RNA into proviral DNA via the viral reverse transcriptase (an RNA-dependent DNA polymerase), and a viral ribonuclease. This reaction takes place in the cytoplasm within 6 hours following virus entry into the cell. The proviral DNA is then inserted into the host genome, a process known as integration. The viral integrase enzyme (a pol gene product) has three functions: it prepares the DNA provirus genome for insertion; it cuts the host cell DNA at the insertion site; and it ligates the viral DNA into the insertion site Figure 13–3. Once integrated, the provirus genome is permanently associated with host cell DNA. An individual remains infected as long as s/he harbors a living cell with integrated proviral DNA. The number of copies of proviral DNA integrated into the host cell genome is not known.
Current Application of CRISPR/Cas9 Gene-Editing Technique to Eradication of HIV/AIDS
Yashwant Pathak in Gene Delivery, 2022
All HIV-1 infected patients have three stages, acute HIV infection, chronic HIV infection (clinical latency), and clinical disease (AIDS) [6]. Mechanistically, HIV1 invades host cells by binding its gp120 envelope protein to the CD4 receptor on the membrane of the target cell, and then interacts with the CCR5 or CXCR4 coreceptor, which depends on the tropism of viral strain. The host cells mainly correspond to T cells, monocytes, and dendritic cells (and even microglial cells, astrocytes, and perivascular macrophages) in the central nervous system. The life cycle of HIV-1 is complex, which contributes to ineffective virus elimination. HIV-1 entry into cells will establish two types of infection, including latent infection and active infection. Latent infection occurs in the early stage of infection within a few cells, while active infection appears in most cells [7]. For active infection, the provirus is active and produces viral particles, which make infected cells bud new progeny virions. The establishment of latent infection may be mediated by complex mechanisms, including RNA interference [8], chromatin environment [9, 10], transcription factors [11], and HIV-1 provirus integration sites [9].
Pathogenicity and virulence of human T lymphotropic virus type-1 (HTLV-1) in oncogenesis: adult T-cell leukemia/lymphoma (ATLL)
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Sanaz Ahmadi Ghezeldasht, David J. Blackbourn, Arman Mosavat, Seyed Abdolrahim Rezaee
Surprisingly, many of those clones in ATLL (around 56%) have two different types of defective provirus, with a higher frequency of type 2 defective HTLV-1 (43%) [98]. Defective provirus type 2 cannot express Tax due to the deletion of the 5′ LTR or the deletion of the second exon. However, the HBZ sequence remains intact and frequently expressed [99]. These types of provirus are integrated into the host genome and seem to comprise a higher number of infected clones than those with complete proviruses. A defective virus may exist via: (1) Tax silencing to evade the host immune responses; (2) gene nonsense mutation or insertion and deletion; (3) LTR loss in 5′-end; and (4) 5′-LTR DNA methylation, which is discussed in various studies [19,100–102]. These clones containing defective HTLV-1 are more proliferative than those intact [90]. Most authors suggest a single integrated HTLV-1 provirus in infected cells, while an in vivo study could not exclude the possibility that some clones have more than one integrated provirus, particularly in the ATLL transformed clones [57,93]. Therefore, it is practically impossible to ignore the role of defective HTLV-1 proviruses in the pathogenesis of HTLV-1-associated diseases. Moreover, in acute and lymphomatous types of ATLL, the frequency of defective provirus was very high compared to the chronic types, demonstrating a close relationship between defective viruses and the progression of aggressive diseases.
Production of CAR T-cells by GMP-grade lentiviral vectors: latest advances and future prospects
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Mansour Poorebrahim, Solmaz Sadeghi, Elham Fakhr, Mohammad Foad Abazari, Vahdat Poortahmasebi, Asma Kheirollahi, Hassan Askari, Alireza Rajabzadeh, Malihe Rastegarpanah, Aija Linē, Angel Cid-Arregui
After attachment and subsequent penetration into host cells, the viral RNA serves as a template for the synthesis of viral cDNA by the reverse transcriptase. During reverse transcription and synthesis of the two DNA strands, sequences from both termini of the RNA are duplicated, generating the long terminal repeats (LTRs), each one with the U3-R-U5 sequence, located at each end of the double-stranded viral DNA; this is then transported to the nucleus. The newly synthesized retroviral DNA integrates into the host DNA and is referred to as the provirus [54]. The provirus replicates during the cell cycle process and subsequently passes to daughter cells. Unlike other members of the Retroviridae family, lentiviruses can productively infect nondividing cells, which make them attractive for gene therapy [55–57]. Finally, progeny viral genomes are transcribed from the integrated DNA and transported to the cytoplasm. The virion acquires its lipid envelope by budding from the plasma membrane. During the budding process, the viral polyproteins are cleaved by the virus protease, producing a mature infectious virion [58].
HIV-1 cure strategies: why CRISPR?
Published in Expert Opinion on Biological Therapy, 2021
Andrew J. Atkins, Alexander G. Allen, Will Dampier, Elias K. Haddad, Michael R. Nonnemacher, Brian Wigdahl
The strategy of block and lock techniques for targeting HIV-1 is to block viral transcription and lock the virus in latency thereby preventing reactivation of the latent reservoir. Key examples of this technique utilize small molecule inhibitors to achieve this outcome (Figure 1C). Examples include the Tat inhibitor didehydro-cortistatin A (dCA) and LEDGINs, small molecules that bind to the LEDGF/p75 binding pocket of HIV-1 integrase [25–27]. Tat inhibition with dCA works by adhering to the TAR-binding domain of Tat thereby inhibiting transactivation of the HIV-1 promoter [27]. LEDGINs work by inhibition of the interaction between LEDGF/p75 and integrase. This has been demonstrated in vitro to cause an increase in the fraction of integrated provirus having a transcriptionally silent phenotype.
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