Novel TAR-Targeting Small Molecules Inhibit HIV-1 Transcription

Abstract

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.

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