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. 2013 Mar 1;2(3):e23472.
doi: 10.4161/onci.23472.

Analysis of NKp30/NCR3 isoforms in untreated HIV-1-infected patients from the ANRS SEROCO cohort

Nicole Prada  1 , Guillemette Antoni, Frédéric Commo, Sylvie Rusakiewicz, Michaela Semeraro, Faroudy Boufassa, Olivier Lambotte, Laurence Meyer, Marie-Lise Gougeon, Laurence Zitvogel
Affiliations

Analysis of NKp30/NCR3 isoforms in untreated HIV-1-infected patients from the ANRS SEROCO cohort

Nicole Prada et al. Oncoimmunology. .

Abstract

Natural killer (NK) cells play a prominent role at the intersection between innate and cognate immunity, thus influencing the development of multiple pathological conditions including HIV-1-induced AIDS. Not only NK cells directly kill HIV-1-infected cells, but also control the maturation and/or elimination of dendritic cells (DCs). These functions are regulated by the delicate balance between activating and inhibiting receptors expressed at the NK-cell surface. Among the former, NKp30 has raised significant interest since the alternative splicing of its intracellular domain leads to differential effector functions, dictating the prognosis of patients bearing gastrointestinal sarcoma, and B7-H6 has recently been identified as its main ligand. Since NKp30 is downregulated in CD56-/CD16+ NK cells expanded in viremic, chronically infected HIV-1+ patients, we decided to investigate the predictive value of NKp30 splice variants for spontaneous disease progression in 89 therapy-naïve HIV-1-infected individuals enrolled in an historical cohort of patients followed since diagnosis (ANRS SEROCO cohort). We found no difference in the representation of NK-cell subsets (CD56bright, CD56dim, CD56neg) in HIV-1-infected patients as compared with healthy subjects. NKp30 downregulation was detected in CD56dim and CD56neg NK-cell subsets, yet this did not convey any prognostic value. None of the NKp30 isoforms did affect disease progression, as measured in terms of time-to-loss of circulating CD4+ T cells, time-to-AIDS-defining events and overall survival. NKp30 isoforms do not seem to play a major role in the outcome of HIV-1 infection, but the heterogeneity of the immuno-virological status of patients at enrollment could have to be taken into account.

Keywords: HIV-1; NK; NKp30 isoforms; immunosurveillance; natural course of infection.

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Figures

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Figure 1. HIV-1+ seroconverters exhibit lower percentage of NK cells expressing NKp30 on their membrane, as compared with healthy donors. (A and B) Frozen peripheral blood mononuclear cells (PBMCs) isolated from HIV-1+ patients and healthy donors (HDs) were stained with CD3, CD16, CD56, γδTCR, NKp30 and NKp46-specific antibodies and analyzed by flow cytometry. (A) Gating procedure and NKp30 and NKp46 expression among natural killer (NK) cells of the indicated subsets (one representative experiment out of 89 is shown). (B) White and gray box plots represent data for HDs (n = 10) and HIV-1+ subjects (n = 74), respectively (middle bars = median values, box plots = 25% and 75% percentiles, whiskers = minimum and maximum values). Statistically significant p values are reported (unpaired, two-tailed Student’s t-test).
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Figure 2. Seroconverters clustered based on NCR3 mRNA expression levels do not differ in terms of relative abundance of NKp30+ NK cells. (A and B) Total RNA was isolated from the peripheral blood mononuclear cells (PBMCs) of HIV-1+ patients and healthy donors (HDs) and quantified by qRT-PCR. (A) HIV-1+ patients were clustered into three groups based on NCR3 expression levels as compared with the HD group (ΔΔCt cluster). The difference between NKp30 levels in HIV+ patients and HDs is reported. (B) Percentage of NKp30+ or NKp46+ natural killer (NK) cells for each of the three patient groups as identified by the ΔΔCt cluster are shown. Middle bars = median values, box plots = 25% and 75% percentiles, whiskers = minimum and maximum values. Statistically significant p values are reported (unpaired, two-tailed Student’s t-test). In the upper panel, p values refer to the difference between each group of HIV-1+ subjects and HDs.
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Figure 3.NCR3 mRNA expression levels neither correlate with the loss of CD4+ T cells nor constitute a prognostic factor for time-to-AIDS or overall survival. For each of the three groups of patients as identified by the ΔΔCt cluster (light gray = High NKp30, dark gray = Inter NKp30, black = Low NKp30), Kaplan-Meier curves for time-to-loss of CD4+ T cells (< 200/mm3) time-to-first AIDS-defining event and survival are shown.
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Figure 4. Patients clustered based on their NKp30 isoform profile do not differ in terms of percentage of NKp30+ NK cells. (A and B) Total RNA was isolated from the peripheral blood mononuclear cells (PBMCs) of HIV-1+ patients and healthy donors (HDs) and quantified by qRT-PCR. (A) HIV-1+ patients were clustered in three groups based on the relative expression levels of the three major NKp30 isoforms (ratio cluster). (B) Percentage of NKp30+ or NKp46+ natural killer (NK) cells for each of the three ratio cluster groups. Boxes = 25% and 75% percentiles, middle bars = median values; whiskers = minimum and maximum values. Statistically significant p values are reported (unpaired, two-tailed Student’s t-test). In the left panel, p values refer to the difference between each of the three groups of HIV-1+ subjects and HD.
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Figure 5. NKp30 isoform profiles do not correlate with the loss of CD4+ T cells and are not a prognostic factor for time-to-AIDS or survival. For each of the three groups of patients as identified by the ratio cluster (green = Low C, blue = High B, violet = High C), Kaplan-Meier curves for time-to-loss of CD4+ T cells (< 200/mm3), time-to-first AIDS-defining event and survival are shown.
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Figure 6. Lack of correlation between the percentages of CD56neg NK cells and clinical parameters. (A and C) Percentage of CD56neg cells among natural killer (NK) cells as a function of CD4+ T-cell counts (A), viral load (B) and proviral DNA levels (C) (Spearman correlation).
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