Journal
JOURNAL OF VIROLOGY
Volume 92, Issue 12, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00235-18
Keywords
natural killer cells; HIV; latency reversal; HIV eradication; immunotherapy; vorinostat; VOR; SAHA; immune function; IL-15; shock and kill; kick and kill; ADCC; latency reversal; NK cell; human immunodeficiency virus; interleukins
Categories
Funding
- Martin Delaney Collaboratory program
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [1UM1AI126619-01]
- National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health [1UM1AI126619-01]
- National Institute on Drug Abuse (NIDA) of the National Institutes of Health [1UM1AI126619-01]
- National Institute of Mental Health (NIMH) of the National Institutes of Health [1UM1AI126619-01]
- Qura Therapeutics [RR024383, AI50410]
- North Carolina Biotech Center [2017-IDG-1025]
- National Institutes of Health [1UM2AI30836-01, 1 S10 OD017984]
- CARE
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [UM1AI126619, P30AI064518, P30AI050410, T32AI007392, R21AI127022] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [K01OD024877, S10OD017984] Funding Source: NIH RePORTER
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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-gamma) 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.
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