Furin Inhibition in HIV Disease

Seth Pincus, MD, Principal Investigator
Iris Lindbergh, PhD
Postdoctoral Fellow
Research Assistant
Technician

Abstract
The HIV envelope glycoprotein precursor, gp160, is cleaved into the mature forms, gp120 and gp41, by the cellular protease furin and furin-like proconvertases. In this application, we will explore the potential of furin inhibition as a therapy for HIV infection. The hypothesis to be tested is that anti-HIV effects of furin inhibition can be obtained at levels that do not cause untoward side effects. This will be tested at both the cellular level and in intact animals. We will present evidence that a stable, small molecule furin inhibitor, hexa-D-arginine (6R), can inhibit the spread of HIV infection in tissue culture in concentrations that do not affect cellular processes, and in another model that D6R can be used in vivo to prevent the cleavage of pseudomonas exotoxin A. These studies suggest that D6R, and related compounds, may be used to treat HIV infections. To study the effects of inhibiting furin or other furin-like proteases on HIV infection, we propose three specific aims.

1. To test the efficacy of furin inhibition on in vitro spread of HIV infection and Env processing

2. To test furin inhibitors in a SCID-mouse model of HIV infection.

3. To use RNAi to determine the relative roles played by furin and other furin-like proconvertases to cleave gp160 in different cell types

These studies have relevance for the development of antiviral therapies, as well as treatments for other conditions in which furin action plays a pathological role. These studies will also help elucidate basic processes by which HIV utilizes the cell it inhabits.

Sponsor: NIH
Duration: 10/03 - 09/05