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Introduction to Cells, DNA, and Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
Virologists know a tremendous amount of detail on the synthesis of viral proteins in cells. Typically, for its replication, the virus first has the cell make “early proteins” that help with the expression of other viral genes and may block proteins from the host cell from being made. Then “late proteins” are made, including proteins needed for the structure of the infectious viral particle (Lostroh 2019).
Evolution of Histone Genes
Published in S. K. Dutta, DNA Systematics, 2019
The other typical pattern found in several species is that the genes for all five histones are closely linked and tandemly repeated (Figure 1). The first genes coding for protein isolated from a eukaryote were the genes coding for the histones synthesized in the cleavage stage of sea urchin embryos.28 There are several hundred gene copies for each histone in the sea urchin which code for the early histone genes. All the genes in the unit are transcribed from the same DNA strand. The same gene order has been maintained over the 180 million years of evolution of the sea urchin species.22 These copies are tandemly repeated and are highly conserved within a species, suggesting that they are constantly undergoing correction by gene conversion. These genes are expressed in early development when large amounts of histone mRNA are required. In addition, there are a number of genes coding for the histones expressed later in development.22 These are organized in a manner reminiscent of the yeast and mammalian histones with the genes dispersed but still linked.29,30 There are a limited number (10 to 20) of genes in this class coding for each histone. The H2a and H2b proteins differ in several amino acids among the early and late proteins but the H3 and H4 proteins have the same amino acid sequence.29,31
Role of High-Risk Human Papillomaviruses in Breast Carcinogenesis
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
The HPV genome is about 7.9 kb in size and encodes early (E) and late (L) proteins and noncoding region (NCR) (Figure 8.1). Early are designated as E1, E2, E4, E5, E6, and E7, and late proteins as L1 and L2. In a host cell, the viral DNA is transcribed as a polycistronic mRNA that is cleaved to yield the different viral proteins. The E1 and E2 genes are expressed first upon viral entry into the host cell, and they encode viral DNA replication proteins (Motoyama et al. 2004). The E5 protein along with E1, E2, and E4 are replication proteins that allow the viral DNA (Figure 8.1) to be replicated as an episome in low copy number (Longworth and Laimins 2004a; Doorbar 2005). During the process of differentiation of epithelial cells, the p670 promoter on viral DNA causes increased expression of E1, E2, E4, and E5 proteins, resulting in increased viral DNA amplification. Therefore, E5 is a viral replication protein that helps in replicating the viral episomal DNA (Moody and Laimins 2009).
Locked and loaded: engineering and arming oncolytic adenoviruses to enhance anti-tumor immune responses
Published in Expert Opinion on Biological Therapy, 2022
Not surprisingly, the choice of animal model can also affect the efficacy prediction of oncolytic Ad for human patients. The most available syngeneic tumor models are murine tumor models, but mouse models are usually not permissive for Ad [229]. Thus, immunodeficient mouse xenograft models are usually used to evaluate oncolytic properties, while immunocompetent mouse tumor models are used to measure immune responses. That creates a problem that we cannot measure the interaction of oncolysis and immune stimulation at the same time in mouse models. Now, there are other immunocompetent animal models, such as the Syrian hamster tumor models that have some degree of permissiveness for Ad [230] or humanized mouse models for oncolytic Ad evaluation [231]. There were also several attempts to identify restriction factors for Ads in murine cells [229,232,233]. Young et al. investigated and excluded the viral infection step, gene transcriptions, mRNA splicing, and viral replication as the restricted points for Ad to complete their viral life cycle. Instead, they identified that significant reduction of late viral mRNA translation in murine cell lines compared to human cell lines. And the expression of Ad L4-100 K protein in trans can partially restore the Ad late protein translation, although not fully recovered when compared to the level in human cell lines [229]. If an Ad fully permissive, immunocompetent mouse model can be developed, it will greatly advance the field with better prediction of oncolytic Ad efficacy and with more available immunological tools on hand.
Process intensification in fed-batch production bioreactors using non-perfusion seed cultures
Published in mAbs, 2019
Andrew Yongky, Jianlin Xu, Jun Tian, Christopher Oliveira, Jia Zhao, Kevin McFarland, Michael C. Borys, Zheng Jian Li
The advantages of perfusion cell culture for achieving high VCD to enhance recombinant protein productivity were realized in the early 1980s.29,30 Perfusion cell culture requires equal volumes of fresh media continuously added and spent media removed, while retaining the cells in the bioreactor by use of perfusion equipment such as alternating tangential flow (ATF) devices, cross-flow filters, centrifuges or settlers.31,32 Thus, a higher VCD and volumetric productivity can be achieved with long durations of up to months compared to fed-batch production cultures with durations of 10–20 days.33,34 Perfusion production cell culture has been successfully applied to produce cells or viruses as the intended product35 and to manufacture some very low titer or unstable proteins and enzymes.34 In addition to perfusion alone, different hybrid modes of perfusion and fed-batch production culture have been studied, including concentrated fed-batch culture36,37 and hybrid fed-batch with perfusion culture for the early cell growth phase and fed-batch for the late protein production phase.38
Oncolytic herpes simplex virus therapy for malignant glioma: current approaches to successful clinical application
Published in Expert Opinion on Biological Therapy, 2019
Lingyang Hua, Hiroaki Wakimoto
GSCs are non-permissive for γ34.5-deleted HSV, while non-stem-like cancer cells from the same patient tumors are permissive [81]. GSCs restrict true late protein synthesis, despite normal viral DNA replication and transcription of all kinetic classes. This block in GSCs is specific for true late translation, as early and leaky late transcripts are translated late in infection, notwithstanding shutoff of cellular protein synthesis. Importantly, expression of Us11, by G47Δ for example, in GSCs rescued the replication of γ34.5-deleted HSV, overcoming a cell type-specific innate response to HSV-1 that limits oncolytic activity in GBM. As described above, the chimeric HCMV-HSV C134 [29] exhibited enhanced killing of CD133+ human GSCs compared with a γ34.5-deleted control HSV, C101 [30].