Novel TAR-Targeting Small Molecules Inhibit HIV-1 Transcription

As of 2023, 39.9 million people were living with Human Immunodeficiency Virus type 1 (HIV-1), with 630,000 deaths per year¹. HIV-1 weakens the immune system, leading to opportunistic infections and Acquired Immune Deficiency Syndrome (AIDS)². Combination antiretroviral therapy (cART) is a current therapy which inhibits multiple steps of the viral life cycle, significantly reducing viral loads³. However, cART lacks a transcriptional inhibitor, allowing the presence of viral proteins, as the HIV-1 transactivator protein Tat continues interacting with TAR, a non-coding stem loop structure at the 5’ LTR of the HIV-1 genome⁴. Thus, this study investigated small, TAR-targeting molecules, identifying two candidates, 102 FA and 110 FA, that inhibit viral transcription in monocytes and T-cells, respectively. Since the effects of 102 FA and 110 FA have been observed separately, we explored their combined effects. We treated HIV-1 infected cells from J1.1 (T-cells) and U1 (monocytic) cell lines, with and without induction, using a combined treatment of 102 FA and 110 FA, and analyzed the effects using western blot analysis for viral proteins. 102 FA and 110 FA, combined, did not significantly reduce viral proteins compared to when they were used separately. Viral protein counts, per our densitometry analysis, also remained similar when latent cells were induced. Therefore, our data indicates that the drugs remain more effective when used separately than when combined, even on induced latent cells. Future studies should explore the various facets of combination drug treatments to create more targeted HIV-1 treatments. 1. What are HIV and AIDS? (2023). HIV.gov. Retrieved July 26, 2024, from https://www.hiv.gov/hiv-basics/overview/about-hiv-and-aids/what-are-hiv-and-aids 2. HIV. (2023). World Health Organization. Retrieved July 26, 2024, from https://www.who.int/data/gho/data/themes/hiv-aids#:~:text=Global%20 situation%20and%20 trends%3A,at%20the%20end%20of%202022 3. Simonetti, F. R., & Kearney, M. F. (2015). Review: Influence of ART on HIV genetics. Current opinion in HIV and AIDS, 10(1), 49–54. https://doi.org/10.1097/COH.0000000000000120 4. Das, A. T., Harwig, A., & Berkhout, B. (2011). The HIV-1 Tat protein has a versatile role in activating viral transcription. Journal of virology, 85(18), 9506–9516. https://doi.org/10.1128/JVI.00650-11I