Natural killer cells in HIV-1 infection: dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates - PubMed (original) (raw)

Natural killer cells in HIV-1 infection: dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates

Domenico Mavilio et al. Proc Natl Acad Sci U S A. 2003.

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Abstract

Natural killer (NK) cells play a central role in host defense against various pathogens. Functional defects of NK cells in HIV-1 infection as a direct effect of abnormal expression or function of inhibitory NK receptors (iNKRs), activating natural cytotoxicity receptors (NCRs), and NKG2D have not yet been described. This study demonstrates an expansion of the functionally defective CD56-/CD16+ population of NK cells in viremic versus aviremic patients. We also demonstrate that in HIV-infected viremic patients, expression of iNKRs was well conserved and that in most cases, there was a trend toward increased expression on NK cells as compared with healthy donors. It was also demonstrated that the major activating NK receptors, with the exception of NKG2D, were significantly down-regulated. In contrast, the expression of iNKRs and activating receptors in HIV-infected individuals whose viremia was suppressed to below detectable levels by highly active antiretroviral therapy for 2 years or longer was comparable to that of healthy donors. Functional tests confirmed that the abnormal expression of the activating receptors and of iNKRs was associated with a markedly impaired NK cytolytic function. This phenomenon is not attributed to a direct HIV-1 infection of NK cells; thus, this study may provide insight into the mechanisms of impaired host defenses in HIV-1 viremic patients.

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Figures

Fig. 1.

Fig. 1.

Phenotypic analysis and functional capability of NK cells. (A) Double fluorescence cytofluorometric analysis with NK cells stained with CD56 PE/CD16 FITC and characterization of the abnormal CD56-/CD16+ subset in fresh (red dot plots) and activated (blue dot plots) NK cells with statistical analysis. This population is markedly represented in HIV-1-positive viremic patients (open circles) and is very minimally represented in healthy donors and in HIV-1-positive aviremic individuals. (B) Graphs of statistical dot plots showing the percentage of the CD56-/CD16+ NK cells subset (freshly isolated, Upper; activated, Lower) in all of the subjects within the three groups studied with median (blue bars) and P value between the cohorts of healthy donors versus viremic patients and viremic versus aviremic patients. HD, healthy donors; VIR, viremic patients; AVIR, aviremic patients. (C) Spontaneous cytolytic activity of NK cells activated with rIL-2 in vitro for 6 days against K562 cell lines at different E/T ratios (2:1, 1:1, and 0.5:1) (Lower). Averages were calculated on 13 healthy donors (black squares) versus 17 viremic patients (green circles) and 16 aviremic patients (red diamonds) with statistical analysis (Upper).

Fig. 2.

Fig. 2.

Expression of iNKRs. Graphs show cytofluorometric analyses of percent of surface expression on freshly isolated (red histograms) and IL-2-activated (blue lines) NK cells in single representative individuals for 13 healthy donors (Left), 17 viremic patients (Center), and 16 aviremic patients suppressed by HAART for >2 years (Right) of the following iNKRs: p58.2, p58.1, p70, LIR1/ILT2, and NKG2A.

Fig. 3.

Fig. 3.

Functional evaluation of iNKRs. Graphs show the functional evaluation of surface expression of the following iNKRs by a redirected killing assay using an FcγR+ P815 target cell line. The following receptors were evaluated: p58.2, p58.1, p70, LIR1/ILT2, and NKG2A. Data are presented as an average of all of the data collected from the uninfected individuals (Left), viremic HIV-infected subjects (Center), and aviremic HIV-infected subjects (Right). E/T ratios are 5:1, 2:1, and 0.5:1. Every graph shows the baseline lysis (open squares), the maximal lysis triggered by anti-CD16 IgG mAb (open circles), and the inhibition of killing driven by the relevant inhibitory NK receptors cotriggered with anti-CD16 IgG mAb (filled diamonds).

Fig. 4.

Fig. 4.

Expression of NCRs and NKG2D. Graphs show cytofluorometric analyses of pattern of surface expression (geometric mean fluorescence) of NCRs on freshly isolated (red histograms) and IL-2-activated (blue lines) NK cells in single representative individuals for 13 healthy donors (Left), 17 viremic patients (Center), and 16 aviremic patients suppressed by HAART for >2 years (Right) of the following activating NK receptors: NKp46, NKp30, NKp44, and NKG2D.

Fig. 5.

Fig. 5.

Functional evaluation of NCRs and NKG2D. Graphs show the functional evaluation of surface expression of the following activating NK receptors by a redirected killing assay using an FcγR+ P815 target cell line: NKp46, NKp30, NKp44, and NKG2D. Data are presented as an average of all of the data collected from the uninfected individuals (Left), viremic HIV-infected subjects (Center), and aviremic HIV-Infected subjects (Right). E/T ratios are 5:1, 2:1, and 0.5:1. Every graph shows the baseline lysis (open squares), the maximal lysis triggered by anti-CD16 IgG-mAb (open circles), and the killing driven by the relevant activating NK receptors (filled diamonds).

Fig. 6.

Fig. 6.

PCR for HIV-1 DNA and secretion of IFN-γ and TGF-β. (A) Copies per microgram (mean) with standard deviation of HIV-1 on PBMCs and fresh and activated purified NK cells in the three cohorts of 9 healthy donors (first group), 12 aviremic patients (second group), and 14 viremic patients (third group). (B) Secretion of IFN-γ (Left) and TGF-β (Right) measured in NK cell culture supernatant after 6 h (freshly isolated NK cells) and 6 days of culture in rIL-2 (activated NK cells) in healthy donors (open bars), viremic patients (filled bars), and aviremic patients (stippled bars).

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