Abstract
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.
Highlights
Active anti-retroviral treatment (HAART) is saving countless lives, its application is accompanied by high financial costs, the emergence of resistant viruses and short- and long-term side-effects
nuclear erythroid 2related factor 2 (Nrf2) turns on anti-oxidant genes in response to pharmaceuticals like oltipratz, environmental agents like heavy metals and cigarette smoke, endogenous agents like nitrous oxide and nitro-fatty acids and even plant products like sulforaphane (SFN) and epigallocatechin gallate (EGCG)
In this work we tested the impact of Nrf2 on human immunodeficiency virus (HIV)
Summary
Active anti-retroviral treatment (HAART) is saving countless lives, its application is accompanied by high financial costs, the emergence of resistant viruses and short- and long-term side-effects. We show for the first time that sulforaphane (SFN), a natural product recognized for its health benefits, blocks HIV infection in macrophages. These cells play a critical role in HIV infection and pathogenesis, forming long-lived viral reservoirs [1, 2] and carrying virus into restricted compartments like the brain [3]. A small but specific subset of these cells may be readily infectable, even in HAART-treated patients [6,7,8,9]. Infected macrophages have been observed in asymptomatic, untreated patients [10] and in HAART-treated individuals [11]. Macrophages can powerfully increase T cell infection [14] and may thereby exacerbate T cell depletion in infected individuals
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