Effect of TAR Binding Molecules on HIV-1 Proviral Transcription

Abstract

Human Immunodeficiency Virus Type 1 (HIV-I) is a retrovirus and causative agent of Acquired Immune Deficiency Syndrome (AIDS). Despite over 38 million people living with HIV, there is no definitive cure. Current treatment options include combination antiretroviral therapy (cART). While cART targets entry, reverse transcription, and integration of HIV-1 RNA into host cells, there is no effective HIV-1 transcription inhibitor. Thus, HIV-1 continues to transcribe viral RNAs, including, non-coding Trans-activating Response element (TAR) RNA. Without a transcription inhibitor, infected persons with HIV-1 will not retain true latency, suggesting the need for novel inhibitors that can specifically target viral transcription.

In this study, we screened a panel of molecules, which bind to HIV-1 TAR RNA, identifying potential candidates, 102FA and 110FA, that effectively inhibit viral transcription in immune cells without any apparent toxicity. This study looked at the effect of these inhibitor molecules on viral protein expression in HIV-1 infected U1 monocyte-derived macrophages (U1 MDMs). Our data show that the viral protein expression levels of p24, Nef, and gp120 decreased upon treatment with 102FA and 110FA in U1 MDMs. Furthermore, we tested the molecules for their effect on the PTEF-b complex in uninfected HEK293 cells. This complex, composed of proteins CDK9 and Cyclin T1, regulates the transcription process in all eukaryotic cells but is targeted by HIV-1 viral proteins to enhance viral transcription. Protein expression levels of CDK9 and Cyclin T1 did not change upon treatment of the HEK293 cells, indicating that these molecules do not impact cellular processes. Collectively, the results suggest that the use of small RNA-binding molecules to inhibit viral transcription could potentially complement existing cART drugs to address the therapeutic gap. Further studies will include replicating data via in-vivo experiments in humanized mouse models.