HIV-1 latency reversal agent boosting is not limited by opioid use

Tyler J. Lilie; Jennifer Bouzy; Archana Asundi; Jessica Taylor; Samantha Roche; Alex Olson; Kendyll Coxen; Heather Corry; Hannah Jordan; Kiera Clayton; Nina Lin; Athe Tsibris

doi:10.1172/jci.insight.185480

HIV-1 latency reversal agent boosting is not limited by opioid use

Tyler J. Lilie,¹ Jennifer Bouzy,¹ Archana Asundi,² Jessica Taylor,² Samantha Roche,² Alex Olson,² Kendyll Coxen,¹ Heather Corry,¹ Hannah Jordan,¹ Kiera Clayton,³ Nina Lin,² and Athe Tsibris⁴

Published October 29, 2024 - More info

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Abstract

Opioid use may impact the HIV-1 reservoir and its reversal from latency. We studied forty-seven virally suppressed people with HIV (PWH) and observed that lower concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that did not reverse latency, synergistically increased the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combined a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, generated significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation, modulated surface activation-induced markers, and altered T cell production of TNFα, IL-2, and IFNγ. HIV-1 reservoirs in PWH contained unspliced and polyadenylated (polyA) virus mRNA, the ratios of which were greater in resting than total CD4⁺ T cells and correct to 1:1 with PMAi exposure. We characterized treated suppressed HIV-1 infection as a period of inefficient, not absent, virus transcription. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe mechanisms of an effective cellular HIV-1 latency reversal program.

HIV-1 latency reversal agent boosting is not limited by opioid use

Tyler J. Lilie,¹ Jennifer Bouzy,¹ Archana Asundi,² Jessica Taylor,² Samantha Roche,² Alex Olson,² Kendyll Coxen,¹ Heather Corry,¹ Hannah Jordan,¹ Kiera Clayton,³ Nina Lin,² and Athe Tsibris⁴

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HIV-1 latency reversal agent boosting is not limited by opioid use

Tyler J. Lilie,1 Jennifer Bouzy,1 Archana Asundi,2 Jessica Taylor,2 Samantha Roche,2 Alex Olson,2 Kendyll Coxen,1 Heather Corry,1 Hannah Jordan,1 Kiera Clayton,3 Nina Lin,2 and Athe Tsibris4

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Tyler J. Lilie,¹ Jennifer Bouzy,¹ Archana Asundi,² Jessica Taylor,² Samantha Roche,² Alex Olson,² Kendyll Coxen,¹ Heather Corry,¹ Hannah Jordan,¹ Kiera Clayton,³ Nina Lin,² and Athe Tsibris⁴