Investigating the HIV-1 Latency Promoting Properties of Sulforaphane
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Issue Date
2022-12
Authors
Paudel, Anisha '22
Degree
MS in Pharmaceutical Sciences
Advisor
Singh, Vir B.
Committee Members
Shah, Manish
Yager, Eric
Yager, Eric
Journal Title
Journal ISSN
Volume Title
Abstract
HIV remains incurable due to its ability to exist as an undetectable latent or silent reservoir in different tissues that are insensitive to antiretroviral therapies and invisible to the immune clearance. So far, efforts to completely eradicate the latent reservoir have been a difficult and unsuccessful task. \342\200\234Block and Lock\342\200\235 is a novel approach for HIV cure that aims to permanently silence the latent reservoir using the latency-promoting agents (LPAs) to block the virus transcription and lock the virus promoter to keep it in the latent phase via epigenetic modifications. Recent reports have suggested Sulforaphane (SFN), an inducer of Nrf-2 (nuclear erythroid 2-related factor) mediated antioxidative signaling, to have an additional anti-HIV property by restricting HIV replication at initial stages. For the reactivation of provirus, activation of NF-kB is indispensable. Existing literature suggests that Nrf-2 may negatively regulate NF-kB activation. Considering these
independent observations, we propose SFN may function as a latency promoting agent by
promoting Nrf-2 signaling in cells latently infected with HIV-1. In our study, we noticed
that SFN treatments significantly reduced the TNF\316\261 induced HIV-1 reactivation in the
latently infected monocytic (THP89-GFP) as well as T-cell lines (J89-GFP). Viral RNA
copy numbers released in the supernatant as well as HIV transcription initiation and
elongation-specific transcripts detected by RT-qPCR were remarkably diminished. HIV
p24 levels were also decreased by SFN treatment. SFN mediated Nrf-2 prevent the
activation of NF-kB induced with TNF-\316\261 treatment that is necessary for the reactivation of
the HIV-1 provirus evident with the immunoblot. This shows that SFN can render the latent
cells resistant to reactivation. Thus, our study provides compelling evidence that SFN possesses latency promoting properties that can be utilized in block-and lock approach to
achieve a functional cure for HIV-1.
Citation
Paudel A. Investigating the hiv-1 latency promoting properties of sulforaphane [thesis]. Ann Arbor (MI): Proquest LLC; 2022. 48 p.
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