Nuclear transit and HIV LTR binding of NF-κB subunits held by IκB proteins: Implications for HIV-1 activation

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Abstract

No effective therapy to eliminate the HIV latently infected cell reservoir has been developed. One approach, "shock and kill", employs agents that activate HIV, subsequently killing the activated infected cells and/or virus. Shock and kill requires agents that safely and effectively activate HIV. One class of activation agents works through classical NF-κB pathways, but global NF-κB activators are non-specific and toxic. There exist two major IκBs: IκBα, and IκBϵ, which hold activating NF-κB subunits in the cytoplasm, releasing them for nuclear transit upon cell stimulation. IκBα was considered the main IκB responsible for gene expression regulation, including HIV activation. IκBϵ is expressed in cells constituting much of the latent HIV reservoir, and IκBϵ knockout mice have a minimal phenotype, suggesting that IκBϵ could be a valuable target for HIV activation and reservoir depletion. We previously showed that targeting IκBϵ yields substantial increases in HIV expression. Here, we show that IκBϵ holds c-Rel and p65 activating NF-κB subunits in the cytoplasm, and that targeting IκBϵ with siRNA produces a strong increase in HIV expression associated with enhanced c-Rel and p65 transit to the nucleus and binding to the HIV LTR of the activating NF-κBs, demonstrating a mechanism through which targeting IκBϵ increases HIV expression. The findings suggest that it may be helpful to develop HIV activation approaches, acting specifically to target IκBϵ and its interactions with the NF-κBs.

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Khan, S. Z., Gasperino, S., & Zeichner, S. L. (2019). Nuclear transit and HIV LTR binding of NF-κB subunits held by IκB proteins: Implications for HIV-1 activation. Viruses, 11(12). https://doi.org/10.3390/v11121162

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