Browsing by Subject "HIV-1"
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Item CHARACTERIZATION OF THE HIV-1 PROVIRAL LANDSCAPE IN PERINATALLY INFECTED EARLY TREATED CHILDREN ON LONG-TERM ANTIRETROVIRAL THERAPY(2022) Hasson, Jenna; Kearney, Mary; Patro, Sean; Boyd, Ann; Hood College Biomedical ScienceAntiretroviral therapy (ART) prevents disease progression in people living with Human Immunodeficiency Virus (HIV) (PLWH). However, off-target effects can result in liver disease, heart disease, diabetes, and more, and there is no accessible cure for the virus. Therefore, understanding the mechanisms for HIV persistence on ART is important to inform strategies for the development of future potential curative inventions. Studies investigating the genetics of integrated HIV genomes (proviruses) in adults revealed the sources of low-level viremia and informed new targets for possible curative strategies. However, little is known about the effect of HIV and long-term ART on the developing immune systems of infants and children. Differences between the immune systems of adults and children may influence mechanisms of viral persistence and immune control, which may be reflected by differences in the HIV proviral genetics. The aim of this thesis research was to characterize the HIV proviral genetic landscape in children on long-term ART and compare it to infants on short-term ART, children on short-term ART, and adults on long-term ART to elucidate any potential differences in the proviral populations that may inform new targets for future cure interventions.Item Investigation of HIV-1 Conserved Components for Genomic Recognition(2020-01-01) Swanson, Canessa Jordan; Summers, Michael F; Chemistry & Biochemistry; BiochemistryGenomic recognition for HIV-1 is an intricate process that requires the coordination of distinct intermolecular interactions between the 5'-leader (5'-L) of the viral genome and the RNA-binding nucleocapsid (NC) domain of the Gag polyprotein. Structural and biophysical studies in combination with in vivo packaging experiments identified the minimal packaging unit within the 5'-L, termed the ?CES (core encapsidation signal), which adopts a unique tandem three-way junction structure and is predicted to function as a nucleation site for Gag multimerization. Identification of the initial high affinity binding sites within the lower three-way junction of the ?CES, coined the ?3WJ-1 revealed a potential mechanism of selective RNA packaging. However, these findings, along with the vast majority of HIV-1 structural biology, stem from investigating the widely utilized laboratory strain known as NL4-3. As a means of interpreting the possibility of a structure-function relationship for the conserved 5'- L the present studies investigate another variant of HIV-1, MAL. Sequence alignment of the ?CES region of the two strains indicates a ninety-one percent sequence homology,while additional evaluation of the ?3WJ-1 illustrated higher sequence identity at ninety- five percent. Isothermal titration calorimetry (ITC) experiments identified that the binding isotherms for both strains are similar, indicating the sequence variations between MAL and NL4-3 do not perturb the mechanism of action for NC binding. Through the utilization of solution-state nuclear magnetic resonance (NMR), nucleotide-specific 2H-labeling, and residual dipolar coupling (RDC) measurements the three-dimensional structure of the MAL_?3WJ-1 was characterized, leading to a more comprehensive understanding of the complexities behind selective packaging of the viral genome.