Studies of the mutagenesis and virus-host interactions of hepadnaviruses and retroviruses
2021-11
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Studies of the mutagenesis and virus-host interactions of hepadnaviruses and retroviruses
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2021-11
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Although viral infection is preventable by vaccination and antiviral treatments are available, up to 1 million people die every year from hepatitis B virus (HBV)-associated liver diseases. In line with this notion, there is an effective vaccine available for feline leukemia virus (FeLV), but FeLV remains a common infection among domesticated cat populations and accounts for many clinical syndromes that typically end with death within 1 to 3 years after the initial diagnosis. Therefore, the need for new antiviral agents for treating human and veterinary viral pathogens exists, even in instances where effective vaccines are available. Reverse transcriptase (RT) is an essential enzyme for the replication life cycle of both retroviruses (i.e., human immunodeficiency virus type 1, HIV-1) and hepadnaviruses (i.e., HBV). Previous studies have shown two types of small molecules possessing anti-HIV-1 activity, mainly through targeting reverse transcriptase (RT) and the reverse transcription pathway - namely viral mutagens (i.e., decitabine, 5-azacytidine and KP1212) and ribonucleotide reductase inhibitors (RNRIs) (i.e., gemcitabine and resveratrol). Our research group has shown that decitabine and gemcitabine can also inhibit FeLV and murine leukemia viruses (MuLV) replication, which are closely related gammaretroviruses. Based upon these observations, Part 1 of this dissertation sought to test following two hypotheses: 1) mutagen and RNRI or the combination of a mutagen and an RNRI will possess potent anti-HBV activity; and 2) distinct antiviral mechanisms can be elicited by a viral mutagen. A family of host proteins, i.e., human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3, A3) proteins, can induce viral mutagenesis, and therefore act as a cellular-based viral mutagen. APOBEC3 family member proteins can deaminate cytosines in single-strand (ss) DNA, which restricts HIV-1, retrotransposons, and other viruses such as HBV, but can cause a mutator phenotype in many cancers. Part 2 of this dissertation sought to characterize the deamination hotspots of APOBEC3 proteins, and to test the hypothesis that deamination hotspots among APOBEC3 family members are defined by both target site sequence and ssDNA structure. Although anti-HBV therapeutic discovery targeting host factors and screening for inhibitors are in progress, there is a significant knowledge gap regarding HBV-host cell interaction. This line of research investigation is critical to public health as HBV infection accounts for 54% of all hepatocellular carcinomas (HCCs), which is notable as it is the second highest cause of cancer-related mortality worldwide. An enhanced understanding of HBV-host cell interactions will help to improve general knowledge of HBV biology, identify potential targets for antiviral intervention to prevent HCC, and provide insights that could prove useful in the early diagnosis of HCC and the discovery of HCC-targeted therapeutics. Part 3 of this dissertation describes the results of an analysis of HBV-infected cells for testing the hypothesis that host genes involved in the cellular antiviral response and HCC development can be identified by transcriptome analysis. Together, the studies conducted in this dissertation serve to lay the foundation for future basic and translational research studies.
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University of Minnesota Ph.D. dissertation. November 2021. Major: Veterinary Medicine. Advisor: Wei Zhang. 1 computer file (PDF); xiv, 201 pages.
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McDaniel, Yumeng. (2021). Studies of the mutagenesis and virus-host interactions of hepadnaviruses and retroviruses. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/260135.
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