Identification of Modulators of HIV-1 and HTLV-1 Proviral Transcription from a Library of FDA Approved Pharmaceuticals.

摘要

Human immunodeficiency virus 1 (HIV-1) and human T-lymphotropic virus 1 (HTLV-1) comprise the two most prevalent human retroviruses. Recent epidemiological data shows that 34 million people are living with HIV-1 worldwide, while an estimated 15 to 20 million people have contracted HTLV-1. HIV-1 infections can lead to acquired immune deficiency syndrome which still causes nearly 20,000 deaths annually in the USA alone. Similarly, HTLV-1 has been implicated as the causative agent in a number of lethal disease conditions, including adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. As these retroviruses lead to high morbidity and mortality conditions in infected individuals, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA approved inhibitors is at the point of proviral transcription. One successful method for identifying novel therapeutics for the treatment of infectious diseases is the repurposing of pharmaceutical compounds that are already approved by the FDA for alternate indications. To this end the screening of large libraries of FDA approved drugs has already been tested in the treatment of Ebola and other emerging infectious diseases. Some of the major benefits of utilizing FDA approved drugs include the fact that the compounds have well established toxicity profiles in humans, approved manufacturing processes, and immediate commercial availability to the target patient populations. Here we demonstrate that pharmaceuticals previously approved by the FDA for other indications can be utilized to either activate or inhibit proviral transcription in HTLV-1 or HIV-1 infections. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, sodium orthovanadate and sunitinib malate were identified as inhibitors of HTLV-1 proviral transcription.