Increased frequency and function of KIR2DL1–3⁺ NK cells in primary HIV‐1 infection are determined by HLA‐C group haplotypes

Abstract

Acquisition and maintenance of NK cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIR) through the interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1(+) and HIV-1(-) individuals were assessed (N=42 and N=40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3+ NK cells. Further analysis showed that KIR2DL1+ NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3+ NK cells. KIR2DL1-3+ NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes as measured by degranulation and cytokine production. These results identify a novel relationship between HLA-C and KIR2DL+ NK cell subsets and demonstrate that HLA-C-mediated licensing modulates NK cell responses to primary HIV-1 infection.

HIV-1-Mediated Downmodulation of HLA-C Impacts Target Cell Recognition and Antiviral Activity of NK Cells

“…It is therefore possible that alterations of MHC class I expression in some viral infections such as HIV-1 infection may lead to the activation of licensed NK cells. This hypothesis is supported by increased frequencies and expansion of NK cells expressing self-inhibitory KIR in patients with acute and primary HIV-1 infection (Alter et al, 2009; Körner et al, 2014). Delayed progression to AIDS was observed in patients carrying a combination of certain subtypes of the inhibitory receptor KIR3DL1 and their cognate HLA-Bw4 ligands (Martin et al, 2007).…”

“…Levels of NK-cell activation and cytokine production were determined through expression of CD107a on the surface of NK cells and intra-cellular detection of TNF-α as previously described (Alter et al, 2004; Körner et al, 2014). PBMC were cultured in the presence or absence of MHC class I devoid target cell line LCL 721.221 (Burlingham et al, 1989) at an effector:target ratio of 5:1 for a total of 6 hours in the presence of 2.5 μg/mL anti-CD107a.…”

Functional advantage of educated KIR2DL1+ natural killer cells for anti-HIV-1 antibody-dependent activation

“…A potential link has also been noted between KIR2DL1 and HIV‐1 disease progression through the demonstration by Korner et al . that KIR2DL1 + NK cells are expanded in primary HIV‐1 infection in individuals carrying the HLA‐C2 ligand . These expanded KIR2DL1 + NK cells also exhibited a functional advantage over KIR2DL1 – NK cells upon stimulation with HLA‐I‐devoid target cells.…”

Natural killer cell heterogeneity: cellular dysfunction and significance in HIV-1 immuno-pathogenesis

“…Notably, NK cells positive for KIR3DL1 confer better cellular function in individuals with HLA-Bw4 than HLA-Bw6 homozygous alleles [99,100], while the protective effect conferred by KIR3DS1-expressing NK cells [101][102][103] is due to their efficient capability to suppress HIV-1 replication [104]. Further, HLA-C-educated NK cells positive for inhibitory KIR2DL1-3, appear to modulate NK cell functionality during primary HIV-1 [105]. In addition to HLA-KIR interaction, KIR copy number greatly impacts the outcome of the disease.…”