Investigation of antiviral strategies targeting Human Immunodeficiency Virus Type I (HIV-1)
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] HIV-1 infection is currently treated with antiretroviral therapy. Three antiviral approaches were investigated to gain understanding on how HIV-1 can be tackled: (1) by KD-247, a neutralizing antibody targeting the third hypervariable (V3) loop of the HIV-1 gp120; (2) by metal nanoparticles (NPs); (3) by reverse transcriptase (RT) inhibitors. A system was established to generate a soluble, bioactive single-chain variable fragment (scFv) of KD-247 and its variants for validation of molecular interactions between KD-247 and the V3 loop. Six promising variants with improved binding to V3 loops from multiple HIV-1 clades were identified and will be further characterized. Virological studies showed that silver NPs inhibited HIV-1 at an early stage of infection and acted as a virucidal agent, suggesting its applicability as microbicide. Findings on multiple inhibition mechanisms of 4?-ethynyl-2-fluoro-2?-deoxyadenosine (EFdA), effects of RT 172K polymorphism, roles of the SAMHD1 host restriction factor on nucleoside RT inhibitors, and characterization of a gammaretroviral RT also provided new insights into the development of more efficacious RT inhibitors. As a whole, these studies have significant implications for the future design of novel therapies to prevent and treat HIV-1 infection.
Access is limited to the University of Missouri-Columbia.