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. 2012 Aug;28(8):844-51.
doi: 10.1089/AID.2011.0253. Epub 2012 May 3.

NKG2C deletion is a risk factor of HIV infection

Rachel Thomas  1 , Hui Zhi Low, Katja Kniesch, Roland Jacobs, Reinhold E Schmidt, Torsten Witte
Affiliations

NKG2C deletion is a risk factor of HIV infection

Rachel Thomas et al. AIDS Res Hum Retroviruses. 2012 Aug.

Abstract

NK cell function is important in the immune response to HIV infection. NKG2C and NKG2A are activating and inhibitory NK cell receptors, respectively, and their only known ligand, HLA-E, demonstrates increased expression in HIV infection and presents at least one HIV-derived peptide. A variation in chromosome 12 exists in which the 16-kb section of DNA encompassing the nkg2c gene is completely absent. DNA samples of 433 HIV-1-infected patients and 280 controls were genotyped by PCR, and revealed an association of the absence variation with a higher risk of HIV infection, as well as faster progression and higher pretreatment viral loads (p<0.05, respectively). Surface NKG2C expression, analyzed by FACS, on the freshly isolated lymphocytes of 20 control and 19 HIV-infected donors revealed that NKG2C expression is genotype dependent in both populations: no NKG2C expression in the -/- groups, intermediate expression in the +/- groups, and highest expression in the +/+ groups. The comparison of NKG2C and NKG2A expression in HIV and control groups (+/- and +/+ included) indicates an increased NKG2C expression on HIV patient NK cells (p<0.05) and decreased inhibitory NKG2A expression on CD8 T cells (p<0.001), and both these effects are more striking in the +/+ genotype (p<0.005). Furthermore, a positive correlation was found between HIV viral load and the proportion of NKG2C(+) NK cells. The increased expression of NKG2C in HIV patients, in combination with the genetic association of the absence variation with an increased susceptibility to HIV infection, higher HIV viral set point, and a faster progression, indicate that NKG2C is important in the defense against HIV infection and progression.

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Figures

FIG. 1.
FIG. 1.
Expression of NKG2C on peripheral blood mononuclear cells (PBMCs). The proportion of NKG2C+ cells is stratified by genotype. Fresh blood samples of 20 control donors and 19 HIV patients were evaluated by four-color FACS for the expression of NKG2C on CD4 T cells (CD3+CD4+), CD8 T cells (CD3+CD8+), and NK cells (CD3-CD56+). The samples were subdivided according to NKG2C genotype: homozygous absence (−/−; dark gray bars), homozygous presence (+/+; black bars), heterozygous (+/−; white bars), and combined heterozygous and homozygous presence (+/− and +/+ ; checked bars). A, B, and C show the genotype-dependent nature of NKG2C expression on the NK cells of three representative HIV patients. The percentages of CD4 T cells, CD8 T cells, and NK cells that express NKG2C are depicted in D and F, and the mean fluorescence intensities in E and G. *p<0.05, **p<0.01, ***p<0.001.
FIG. 2.
FIG. 2.
Comparison of NKG2C expression in control and HIV patients. HIV patients show increased NKG2C expression on NK cells, and this increase is proportional to genotype. CD8 T cells (CD3+CD8+) and NK cells (CD3-CD56+) freshly isolated from 18 control (hatched bars; +/− n=4, +/+ n=14) and 16 HIV patients (diagonally striped bars; +/− n=5, +/+ n=11) were evaluated for NKG2C expression. Only individuals carrying at least one copy of NKG2C (+/− and +/+) were included. The percentage of NKG2C positive cells and the MFI are depicted in A and B, respectively. The HIV patients and controls were also subdivided according to genotype, and NKG2C expression on NK cells is presented in C and D. *p<0.05, **p<0.01, ***p<0.001.
FIG. 3.
FIG. 3.
Comparison of NKG2A expression in control and HIV patients. HIV patients show decreased NKG2A expression on CD8 T cells, and this increase is proportional to genotype. CD8 T cells (CD3+CD8+) and NK cells (CD3-CD56+) freshly isolated from 18 control (hatched bars; +/− n=5, +/+ n=13) and 12 HIV patients (diagonally striped bars; +/− n=4, +/+ n=8) were evaluated for NKG2A expression. Only individuals carrying at least one copy of NKG2C (+/− and +/+) were included. The percentages of NKG2A positive cells and the MFI are depicted in A and B, respectively. The HIV patients and controls were also subdivided according to genotype, and NKG2A expression on CD8 T cells is presented in C and D. *p<0.05, **p<0.01, ***p<0.001.
FIG. 4.
FIG. 4.
The expression of NKG2C and NKG2A in relation to HIV viral load. The percentages of freshly isolated NK cells (CD3-CD56+) of HIV patients expressing NKG2C (A) and NKG2A (B) were plotted against the viral load of the patient corresponding to the time the sample was taken. All subjects included are of the +/+ genotype.
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