Abstract
Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, 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 modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. 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, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators.
Highlights
Retroviruses are difficult-to-treat pathogens that integrate their viral genome into the host’s DNA and induce numerous disease states in those infected, many of which can be severely adverse
The primary culprit for the inability of highly active antiretroviral therapy (HAART) to purge all infected cells is the reservoir of latently infected cells that predominantly consists of the long-lived resting memory CD4+ T cells [14,15,16], numerous other cell types contribute to this latent population [17,18,19,20,21,22]
A similar trend was observed in OM10.1 myleoid cells where a dramatic increase in polymerase II (Pol II), Cdk9, p65 and Baf200 (~1.5–3.0 fold) factor occupancy was observed in these cells
Summary
Retroviruses are difficult-to-treat pathogens that integrate their viral genome into the host’s DNA and induce numerous disease states in those infected, many of which can be severely adverse. AIDS-related causes kill nearly 20,000 people in the USA per year and HIV-associated neurocognitive disorders (HAND) are diagnosed in up to 47% of patients despite the use of highly active antiretroviral therapy (HAART) [1,2]. The latent viral pool within the quiescent memory CD4+ T cells is highly persistent in the host with a half-life of up to 44 months for patients on HAART and no detected recurrence of viremia [24]. Since current therapeutics only block the transmission of the virus and do not address the cells that already harbor the integrated provirus; the latent pool of infected cells can re-establish active viral spread whenever HAART treatment is ceased
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