Controlling HIV release from cells with first-in-class drugs targeting virus budding

This proposal has the potential to create a new game changing strategy to clinically treat pathogenic enveloped virus infections in humans including HIV with first-in-class drugs, referred to as Viral Budding Inhibitors (VBIs). These drugs would act by blocking the budding of enveloped viruses which use a common mechanism to release particles from cell plasma membranes. This causes particles to accumulate on the cell surface, which increases detection of infected cells by the natural immune system. Moreover, because particles are trapped on the cell surface, titers of viruses in the plasma fall, slowing down the spread of infection to uninfected cells. This allows the immune system more time to clear the infection. Unique high throughput screening methods were used to identify several VBI compounds which disrupt virus budding by inhibiting the interaction of viral L-domain motifs with cellular Tsg101 and Nedd4 proteins, respectively. Two of these were shown to block budding of HIV and ASLV (lenti- and α-retrovirus, respectively) from cells in culture. Experiments are planned to improve potency of VBIs without increasing cell toxicity, test the activity of the Tsg101 targeting drugs against HIV infections, perform animal model testing of VBIs to control HIV infections, and quantify rates of appearance of drug resistance in HIV-1 infected cells treated with the most potent VBIs.