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J Virol. 2018 May 29;92(12). pii: e00235-18. doi: 10.1128/JVI.00235-18. Print 2018 Jun 15.

Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency Reversal Ex Vivo.

Author information

1
UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
4
Department of Surgery and Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
5
UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA dmargo@med.unc.edu.
6
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Abstract

Current efforts toward human immunodeficiency virus (HIV) eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8+ T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of interleukin 15 (IL-15) treatment on NK cell function and the potential for stimulated NK cells to clear the HIV reservoir. We measured NK cell receptor expression, antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxicity, interferon gamma (IFN-γ) production, and antiviral activity in autologous HIV replication systems. All NK cell functions were uniformly improved by IL-15, and, more importantly, IL-15-treated NK cells were able to clear latently HIV-infected cells after exposure to vorinostat, a clinically relevant latency-reversing agent. We also demonstrate that NK cells from HIV-infected individuals aviremic on antiretroviral therapy can be efficiently stimulated with IL-15. Our work opens a promising line of investigation leading to future immunotherapies to clear persistent HIV infection using NK cells.IMPORTANCE In the search for an HIV cure, strategies to enhance immune function to allow recognition and clearance of HIV-infected cells following latency reversal are being evaluated. Natural killer (NK) cells possess characteristics that can be exploited for immunotherapy against persistent HIV infection. We demonstrate that NK cells from HIV-positive donors can be strongly stimulated with IL-15, improving their antiviral and cytotoxic potential and, more importantly, clearing HIV-infected cells after latency reversal with a clinically relevant drug. Our results encourage further investigation to design NK cell-based immunotherapies to achieve HIV eradication.

KEYWORDS:

ADCC; HIV; HIV eradication; IL-15; NK cell; SAHA; VOR; human immunodeficiency virus; immune function; immunotherapy; interleukins; kick and kill; latency reversal; natural killer cells; shock and kill; vorinostat

PMID:
29593039
PMCID:
PMC5974478
DOI:
10.1128/JVI.00235-18
[Indexed for MEDLINE]
Free PMC Article

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