Browsing by Subject "HIV-2"
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Item Studies On The Antiretroviral Mechanism Of Action Of Clofarabine(2014-07) Beach, LaurenSince the beginning of the AIDS epidemic over thirty years ago, human immunodeficiency virus type 1 (HIV-1) has infected seventy-five million people and has claimed the lives of over thirty-six million people worldwide, making HIV/AIDS one of the most devastating global infectious disease epidemics in history. To date, no preventative vaccine or curative treatment exists for HIV-1 infection. The availability of drugs to treat HIV-1 infection has led to drug resistance, which limits the utility of antiviral therapy. This has provided the basis for the continual need for identifying new targets for antiviral drugs. This dissertation investigated the antiretroviral activity and mechanism of action for clofarabine, a purine nucleoside antimetabolite. Clofarabine was demonstrated to exert antiretroviral activity against both HIV-1 and human immunodeficiency virus type 2 (HIV-2). Studies directed at elucidating the antiretroviral mechanism of action support a model in which clofarabine acts as an inhibitor of ribonucleotide reductase, leading to imbalances in cellular dNTP pools, which reduces viral infectivity through an increase in the HIV-1 mutation rate.Item Studies on the Molecular Determinants of Human Retrovirus Diversity(2021-09) Meissner, MorganThe human immunodeficiency viruses (HIVs) are two species (HIV type 1, HIV-1; HIV type 2, HIV-2) in the Lentivirus genus of the Retroviridae family of viruses and are the etiological agents of acquired immunodeficiency syndrome (AIDS). Nearly 75 million people have been infected with HIV-1 and HIV-2 since their emergence in the human population and they are responsible for the deaths of almost 32 million individuals to date. One of the key drivers of the HIV-1 pandemic is the extreme genetic diversity of the virus, which drives the development of antiviral drug resistance and frustrates vaccine development. Retroviruses also exhibit considerable structural diversity, which may have important implications for infectivity and replication. Human T-cell leukemia virus type 1 (HTLV-1), within the Deltaretrovirus genus, is also a major pathogenic human retrovirus. HIV-2 and HTLV-1 exhibit markedly reduced rates of transmissibility and potentially evolution compared with HIV-1 and are therefore understudied relative to their pandemic counterpart. The overarching goal of this thesis was to characterize the viral and cellular determinants of the molecular diversity of human retroviruses, with an emphasis on HTLV-1 and HIV-2. To this end, experiments were conducted which 1) characterized the structural diversity of authentic HTLV-1 particles derived from the chronically infected SP cell line, demonstrating that intact capsid cores are relatively rare among HTLV-1 particles; and 2) examined the contribution of host apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins to HIV-2 mutagenesis, which revealed that despite their role as potent mutagens of HIV-1, APOBEC3-mediated mutagenesis of HIV-2 is limited. Additionally, a user-friendly sequence analysis workflow was developed that enables the ultra-accurate detection of mutations within HIV-1 and HIV-2, which reduces the background error rate of traditional Illumina next-generation sequencing by approximately 100-fold. This workflow is already being employed to characterize the contributions of additional cellular proteins to retroviral mutagenesis, including the host protein SAM domain and HD domain- containing protein 1 (SAMHD1). Taken together, these studies provide new insights into the structural and genetic diversity of human retroviruses, particularly those which have historically been poorly characterized and underappreciated.