Targeting NK cell activity to eradicate the HIV-1 reservoir

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Antiretroviral therapy (ART) has been effective in the suppression of HIV-1 viremia, but does not eliminate the reservoir of cells with latent HIV-1 infection, obligating lifelong therapy. Recent work has identified mechanisms for activating HIV-1 transcription in latently infected cells without inducing cellular activation, including the use of histone deacetylase (HDAC) inhibitors. This offers a pathway towards potential eradication of the viral reservoir and cure of the infection. However reactivation of HIV-1 transcription alone is insufficient to induce cell death via viral cytopathic effects, supporting the need for immune-mediated surveillance and killing of infected cells. Given the need for rapid recognition and elimination of infected cells, we propose targeting NK cells as an innate effector population poised for immediate function. Although NK cells have been shown to have an important role in HIV-1 infection, they have not been a focus of investigations for reservoir eradication. As a cytotoxic cell population capable of recognizing generic signals of cellular stress triggered by viral replication with rapid effector function, NK cells are well suited to identification of cellular stress induced by HIV-1 gene transcription. These studies will specifically examine the induction of NKG2D ligands on latently infected cells after activation of HIV-1 transcription, and examine the functional consequences for NK cell-mediated killing. In an effort to enhance targeting specifically to HIV-1-infected cells, reactivation will be paired with experiments designed to inhibit Nef, an HIV-1 protein known to reduce the expression of MHC class I and NKG2D ligands. This novel approach combines virus activation with a strategy to enhance host cell targeting. If successful, the innovative basic studies proposed here would offer the basis for preclinical and clinical trials aimed at reservoir eradication.