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S100A14 Is Increased in Activated NK Cells and Plasma of HIV-Exposed Seronegative People Who Inject Drugs and Promotes Monocyte–NK Crosstalk

Colón, Krystal, PhD*; Speicher, David W., PhD; Smith, Peter, BA; Taylor, Mack, BA; Metzger, David S., PhD; Montaner, Luis J., DVM, DPhil*; Tomescu, Costin, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: February 1, 2019 - Volume 80 - Issue 2 - p 234–241
doi: 10.1097/QAI.0000000000001911
Basic Science
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Background: HIV-exposed seronegative people who inject drugs (HESN-PWID) have been shown to have increased natural killer (NK) cell and myeloid activation when compared with control donors.

Methods: We investigated potential mechanisms maintaining NK activation by conducting quantitative proteome comparisons of NK cells from HESN-PWID subjects and control donors. Proteins upregulated in NK cells were measured in the plasma of HESN-PWID subjects by ELISA and further investigated for their ability to induce innate immune activation in vitro.

Results: The NK cell proteome comparison showed markedly higher levels of interferon-stimulated proteins and S100 proteins, including S100A14. Consistent with these results, we observed significantly higher levels of S100A14 in the plasma of HESN-PWID subjects compared with controls (P = 0.033, n = 25). In vitro, the addition of recombinant S100A14 protein significantly activated NK cells in a peripheral blood mononuclear cell mixture (P = 0.011, n = 9), but not purified NK cells alone. Treatment of purified monocytes with recombinant S100A14 protein induced secretion of TNF-alpha and led to significantly higher NK CD69 activation (P = 0.0156, n = 7) in a co-culture through a TLR4-dependent interaction.

Conclusions: Our study identified S100A14 as a novel protein increased within NK cells and plasma of HESN-PWID subjects with the capacity to sustain NK activation through TLR4-dependent activation of myeloid cells.

*HIV Immunopathogenesis Laboratory, The Wistar Institute, Philadelphia, PA;

Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA; and

HIV Prevention Division, Department of Psychiatry, The University of Pennsylvania, Philadelphia, PA.

Correspondence to: Costin Tomescu, PhD and Luis J. Montaner, DVM, PhD, The Wistar Institute, 3601 Spruce Street, Room 480, Philadelphia, PA 19104 (e-mail: ctomescu@wistar.org).

Supported by the following grants from the National Institutes of Health (R21DA040554, T32AI007632, UM1AI126620, R01AI094603, R01DA028775, P30CA010815, and P30AI045008). Additional support was provided by The Philadelphia Foundation (Robert I. Jacobs Fund), Kean Family Professorship, Henry S. Miller, Jr. and J. Kenneth Nimblett, AIDS funds from the Commonwealth of Pennsylvania and from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health, the Penn Center for AIDS Research (P30 AI 045008), and Cancer Center Grant (P30 CA10815). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Presented at: SLB; 2017; Vancouver, BC, CA, and CROI; 2018; Boston, MA.

The authors have no funding or conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Received June 05, 2018

Accepted October 22, 2018

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