Medicine and Health Sciences Commons^™

The Role Of The Host Factor Sptbn1 In Hiv-1 Infection Of Microglial Cells, Marc Gordon Havlicek

MSU Graduate Theses

HIV-1 is the etiological agent that cause AIDS. Since the 1980’s when HIV-1 was discovered, much has been discovered, however a cure for HIV-1 has eluded researchers. Effective therapeutics do exist but can have adverse side effects including HAND/HAD which leads to neurodegeneration in patients regardless of viral suppression. One area of research that holds the possibility of discovering new viral targets and therapeutics is host factor interaction within the replication process. One host factor that can cause a decrease in HIV-1 infectivity is SPTBN1. SPTBN1 is a cytoskeletal protein that was shown to bind to the capsid and nucleocapsid …

The Role Of Actin Associated Sptbn1 Host Factor In Hiv-1 Infection In Microglial Cells, Hannah Matheney

MSU Graduate Theses

Human immunodeficiency virus (HIV) is a chronic illness affecting more than 32.7 million individuals worldwide. The virus infects immune cells, weakening the immune system overtime eventually leading to acquired immunodeficiency syndrome (AIDS) if left untreated. Infection starts with a fusion step, followed by uncoating of the HIV capsid once in the cytoplasm of the cell. HIV uses host cell proteins to complete the infection process, like the actin associated factor, SPTBN1. The Hulme lab has previously shown that SPTBN1 knockdown by siRNA in microglial cells decreased HIV infection and delayed uncoating of HIV. Because fusion is prior to uncoating, it …

Role Of Cyclophilin A And Trim5Α In Hiv-1 Infection And Capsid Uncoating, Emma Lk Wise

MSU Graduate Theses

Microglial cells are immune cells that protect the central nervous system and are subject to HIV- 1 infection. HIV-1 infection of these cells can lead to HIV Associated Neurocognitive Disorders (HAND). Since HIV-1 only codes for 15 different proteins, the virus also uses cellular factors, like Cyclophilin A (CypA), to assist in viral replication. The cell also has antiretroviral restriction factors, like tripartite motif-containing protein 5 (TRIM5α), to protect against infection. The goal of this project is to investigate the role of CypA in the early steps of HIV-1 replication and TRIM5α restriction in microglial cells. I hypothesize that CypA …

Hiv-1 Drug Resistance To Integrase Strand Transfer Inhibitors In Hiv-1 Non-B Subtypes, Emmanuel Ndashimye

Electronic Thesis and Dissertation Repository

Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low-and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation …

Tobacco/Hiv-1-Induced Myeloid Cell-Derived Extracellular Vesicles In Hiv-1 Pathogenesis, Sanjana Haque

Theses and Dissertations (ETD)

Introduction. Smoking, which is highly prevalent in people living with HIV/AIDS, has been shown to exacerbate HIV-1 replication, in part via cytochrome P450 (CYP)-induced oxidative stress. CYP enzymes metabolize cigarette smoke condensate (CSC), causing oxidative stress and cytotoxicity. Our previous studies have demonstrated that CSC and specific CSC constituents, benzo(a)pyrene and nicotine, potentially induce CYPs, resulting in higher oxidative stress and subsequent exacerbation of HIV-1 replication in monocytes and macrophages. However, the exact mechanism behind tobacco-induced, oxidative stress-mediated enhancement of HIV-1 replication is still poorly understood. Extracellular vesicles (EVs) have recently gained attention for their unique nature as intercellular messengers …

Determining The Relative Transmission Fitness Of Hiv-1 Subtypes A, B, C, And D, Spencer Yeung

Electronic Thesis and Dissertation Repository

There is in vivo evidence that suggests the genetic diversity of HIV-1 subtypes influence heterosexual transmission efficiency. To recapitulate sexual transmission in vitro, blocks of genital tissue were exposed to mixtures of genetically different subtype viruses. Migrating immune cells were collected and co-cultured with a CD4+ T-cell line permissive to HIV infection (PM1) to measure dendritic cell virus transfer; HIV-exposed tissues were cultured separately. Next generation sequencing (NGS) of HIV-1 DNA was used to quantify relative infection rates of the various challenge viruses, and to assess fitness differences in infection of the tissue vs. migratory/T cell co-cultures. Our results …

Designing An Optimal Hiv-1 Env Immunogen For The Vesicular Stomatitis Virus Vaccine Platform And Elucidating The Role Of Hiv-1 Nef In Env Trafficking, Jason Knapp

Electronic Thesis and Dissertation Repository

Current vesicular stomatitis virus (VSV)-based HIV vaccines require an optimal HIV envelope immunogen to improve protection in vivo. Furthermore, the involvement of viral proteins, such as HIV Nef, in the trafficking of HIV Env to sites of viral assembly remains poorly understood and may provide additional insights for the design of a VSV-based HIV vaccine. We constructed new codon-optimized chimeric Env immunogens containing the signal sequence of honeybee melittin and the transmembrane and cytoplasmic tail domains of SIV, Zaire Ebola, or VSV glycoproteins. We showed that all chimeric Env immunogens had enhanced expression levels within producer cells. Utilizing bimolecular …

Development Of A Long-Acting Nanoformulation Of Dolutegravir For Prevention And Treatment Of Hiv-1 Infection, Brady Sillman

Theses & Dissertations

Dolutegravir (DTG) is a potent human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to viral drug resistance. However, opportunities to improve its profile abound. These include extending the drug’s apparent half-life, increasing penetrance to “putative” viral reservoirs, and reducing inherent toxicities. These highlight, in part, the need for long-acting, slow effective release antiretroviral therapy (LASER ART) delivery schemes. A long-acting (LA) DTG was made by synthesizing a hydrophobic and lipophilic prodrug encased with poloxamer (P407) surfactant. This modified DTG (MDTG) reduced systemic metabolism and polarity, increased lipophilicity and membrane permeability, improved encapsulation, and formed …

Hiv-1 Group M Subtype Fitness, Disease Progression, And Entry Efficiency, Colin M. Venner

Electronic Thesis and Dissertation Repository

Human immunodeficiency virus type 1 (HIV-1) emerged in the human population shortly after the turn of the 19th century. Distribution of HIV-1 across the globe over the past 30–35 years can be traced to founder events with primordial HIV strains from sub-Saharan Africa. Even considering the burden of HIV in Africa, our knowledge of HIV-1 disease is still largely limited to subtype B HIV-1, a strain responsible for 3 million infections in North America and Europe as compared to the 33 million that are infected with HIV-1 subtypes A, C, D, and circulating and unique recombinant forms.

This dissertation analyzes …