Investigation of antiviral strategies targeting Human Immunodeficiency Virus Type I (HIV-1)

[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

Drug Interactions in Lenacapavir-Based Long-Acting Antiviral Combinations

Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV agents such as lenacapavir (a capsid-targeting antiviral) and islatravir (EFdA, a nucleoside reverse transcriptase translocation inhibitor) need to be explored as combination therapies. Therefore, we sought to determine whether combination of lenacapavir with islatravir, rilpivirine, or cabotegravir displayed synergy, additivity, or antagonism. We performed dose-response matrices of these drug combinations in an HIV-1 reporter cell line and subsequently analyzed the data with SynergyFinder Plus, which employs four major drug interaction models: highest single agent, Bliss independence, Loewe additivity, and zero interaction potency. Most of these models predict additive inhibition by the studied drug combinations This work highlights the importance of effective drug combinations in LA-regimens