Grant: Fellowship - Priority Announcement - HIV/AIDS and/or STBBI

Antiretroviral therapies (ARTs) for HIV-1 infection target the viral lifecycle and delay the progression of those infected to AIDS. However, the effectiveness of these ARTs are plagued by a rise in drug-resistant HIV strains present in over 7-24% of newly infected people in the US and Europe. This issue calls for new approaches in combating HIV-1 infection. Several studies have demonstrated that delivering agents towards this stage, which is not targeted by current ARTs termed HIV-1 RNA processing, can successfully inhibit HIV-1 growth. Two of these inhibitors (digoxin and chlorhexidine) are already FDA-approved drugs for other purposes. Although chlorhexidine is not suitable for systemic use, concentrations of digoxin required to inhibit HIV replication in T cells cultured from HIV-infected patients are within accepted dosage levels used to treat heart conditions. Furthermore, I discovered that one digoxin derivative (digitoxigenin) and compound 191 are both potent inhibitors of HIV-1 RNA processing with improved safety profiles over digoxin. All of these studies, however, were performed in cell culture and these findings may not be transferable to patients. Whether this approach can become a novel ART for treating HIV-1 infection remains to be determined. In this proposal, I plan to investigate if these HIV-1 RNA processing inhibitors are effective against HIV-1 infection in an environment that mimics humans known as "humanized mice." These mice will be infected with HIV-1 and treated with inhibitors to test their ability to inhibit HIV-1 growth in comparison to current ARTs. Successful generation of a humanized mouse model could complement drug screening efforts by supporting their validation in animal models, bringing discoveries one step closer to potential clinical trials. Moreover, this model could also support global efforts in combating other deadly diseases, particularly ones involving human immunodeficiencies, and viruses, such as Zika and Influenza.