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DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection?
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Potential of the NKG2D/NKG2DL Axis in NK Cell-Mediated Clearance of the HIV-1 Reservoir

Academic Department of Pediatrics, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
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Int. J. Mol. Sci. 2019, 20(18), 4490; https://doi.org/10.3390/ijms20184490
Received: 31 July 2019 / Revised: 2 September 2019 / Accepted: 9 September 2019 / Published: 11 September 2019
(This article belongs to the Special Issue Advances in NK Cell Receptors and Their Ligands)
Viral persistency in latently infected CD4+ T cells despite antiretroviral therapy (ART) represents a major drawback in the fight against HIV-1. Efforts to purge latent HIV-1 have been attempted using latency reversing agents (LRAs) that activate expression of the quiescent virus. However, initial trials have shown that immune responses of ART-treated patients are ineffective at clearing LRA-reactivated HIV-1 reservoirs, suggesting that an adjuvant immunotherapy is needed. Here we overview multiple lines of evidence indicating that natural killer (NK) cells have the potential to induce anti-HIV-1 responses relevant for virus eradication. In particular, we focus on the role of the NKG2D activating receptor that crucially enables NK cell-mediated killing of HIV-1-infected cells. We describe recent data indicating that LRAs can synergize with HIV-1 at upregulating ligands for NKG2D (NKG2DLs), hence sensitizing T cells that exit from viral latency for recognition and lysis by NK cells; in addition, we report in vivo and ex vivo data showing the potential benefits and drawbacks that LRAs may have on NKG2D expression and, more in general, on the cytotoxicity of NK cells. Finally, we discuss how the NKG2D/NKG2DLs axis can be exploited for the development of effective HIV-1 eradication strategies combining LRA-induced virus reactivation with recently optimized NK cell-based immunotherapies. View Full-Text
Keywords: HIV-1 eradication; natural killer (NK) cells; NKG2D; latency reversing agents; immunotherapy HIV-1 eradication; natural killer (NK) cells; NKG2D; latency reversing agents; immunotherapy
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Desimio, M.G.; Covino, D.A.; Doria, M. Potential of the NKG2D/NKG2DL Axis in NK Cell-Mediated Clearance of the HIV-1 Reservoir. Int. J. Mol. Sci. 2019, 20, 4490.

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