Research Article: Sulforaphane Inhibits HIV Infection of Macrophages through Nrf2

Date Published: April 19, 2016

Publisher: Public Library of Science

Author(s): Andrea Kinga Marias Furuya, Hamayun J. Sharifi, Robert M. Jellinger, Paul Cristofano, Binshan Shi, Carlos M. C. de Noronha, Ronald Swanstrom.


Marburg virus, the Kaposi’s sarcoma-associated herpesvirus (KSHV) and Dengue virus all activate, and benefit from, expression of the transcription regulator nuclear erythroid 2-related factor 2 (Nrf2). The impact of Nrf2 activation on human immunodeficiency virus (HIV) infection has not been tested. Sulforaphane (SFN), produced in cruciferous vegetables after mechanical damage, mobilizes Nrf2 to potently reprogram cellular gene expression. Here we show for the first time that SFN blocks HIV infection in primary macrophages but not in primary T cells. Similarly SFN blocks infection in PMA-differentiated promonocytic cell lines, but not in other cell lines tested. siRNA-mediated depletion of Nrf2 boosted HIV infectivity in primary macrophages and reduced the anti-viral effects of SFN treatment. This supports a model in which anti-viral activity is mediated through Nrf2 after it is mobilized by SFN. We further found that, like the type I interferon-induced cellular anti-viral proteins SAMHD1 and MX2, SFN treatment blocks infection after entry, but before formation of 2-LTR circles. Interestingly however, neither SAMHD1 nor MX2 were upregulated. This shows for the first time that Nrf2 action can potently block HIV infection and highlights a novel way to trigger this inhibition.

Partial Text

Highly active anti-retroviral treatment (HAART) is saving countless lives, however its application is accompanied by high financial costs, the emergence of resistant viruses and short- and long-term side-effects. A better understanding of how to activate cellular anti-viral defenses promises new therapeutic alternatives to overcome these limitations and to support prevention and cure strategies.

Here we have, for the first time, shown that SFN stops HIV infection in primary macrophages by triggering a block to infection that impacts the virus after reverse transcription but before 2-LTR circle formation. The SFN-regulated restriction relies on Nrf2, a transcription regulator of anti-oxidant genes. Importantly, we found that macrophages express sufficient Nrf2 to maintain a partial restriction even in the absence of SFN. This underscores that the anti-viral activity, while significantly enhanced by SFN through its augmentation of Nrf2 levels, does not require SFN to function.




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