Abstract
Accumulating evidence suggests an important role for Natural Killer (NK) cells in the control of HIV-1 infection. Recently, it was shown that NK cell-mediated immune pressure can result in the selection of HIV-1 escape mutations. A potential mechanism for this NK cell escape is the selection of HLA class I-presented HIV-1 epitopes that allow for the engagement of inhibitory killer cell immunoglobulin-like receptors (KIRs), notably KIR2DL2. We therefore investigated the consequences of sequence variations within HLA-Cw*0102-restricted epitopes on the interaction of HLA-Cw*0102 with KIR2DL2 using a large panel of overlapping HIV-1 p24 Gag peptides. 217 decameric peptides spanning the HIV-1 p24 Gag consensus sequence were screened for HLA-Cw*0102 stabilization by co-incubation with Cw*0102(+)/TAP-deficient T2 cells using a flow cytometry-based assay. KIR2DL2 binding was assessed using a KIR2DL2-IgG fusion construct. Function of KIR2DL2(+) NK cells was flow cytometrically analyzed by measuring degranulation of primary NK cells after co-incubation with peptide-pulsed T2 cells. We identified 11 peptides stabilizing HLA-Cw*0102 on the surface of T2 cells. However, only one peptide (p24 Gag209–218 AAEWDRLHPV) allowed for binding of KIR2DL2. Notably, functional analysis showed a significant inhibition of KIR2DL2(+) NK cells in the presence of p24 Gag209–218-pulsed T2 cells, while degranulation of KIR2DL2(−) NK cells was not affected. Moreover, we demonstrated that sequence variations in position 7 of this epitope observed frequently in naturally occurring HIV-1 sequences can modulate binding to KIR2DL2. Our results show that the majority of HIV-1 p24 Gag peptides stabilizing HLA-Cw*0102 do not allow for binding of KIR2DL2, but identified one HLA-Cw*0102-presented peptide (p24 Gag209–218) that was recognized by the inhibitory NK cell receptor KIR2DL2 leading to functional inhibition of KIR2DL2-expressing NK cells. Engagement of KIR2DL2 might protect virus-infected cells from NK cell-mediated lysis and selections of sequence polymorphisms that increase avidity to KIR2DL2 might provide a mechanism for HIV-1 to escape NK cell-mediated immune pressure.
Highlights
Natural Killer (NK) cells play a pivotal role in the first line innate immune response to viral infections through the killing of virus-infected cells and modulation of adaptive immunity [1,2,3]
Upon viral infection the peptide repertoire presented by human leukocyte antigen (HLA) class I molecules changes, potentially providing signals that result in recognition and elimination of the infected cell by the host immune system
Our findings help to elucidate the complex interaction between killer cell immunoglobulin-like receptors (KIRs) molecules, such as KIR2DL2, and HLA/peptide complexes and provide a foundation for further studies investigating the role of sequence variations within HIV-1 epitopes on HLA/KIR interactions, and the ability of viruses to evade NK cellmediated recognition
Summary
Natural Killer (NK) cells play a pivotal role in the first line innate immune response to viral infections through the killing of virus-infected cells and modulation of adaptive immunity [1,2,3] Their function is controlled by a number of surface receptors, including activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) that interact with human leukocyte antigen (HLA) class I molecules expressed on target cells [4]. While it was known that expression of HLA-B alleles with the serological Bw4 motif (HLA-Bw4) is protective in HIV-1 infection [7,8], Martin et al first demonstrated that the combined presence of alleles encoding for the activating receptor KIR3DS1 and HLA-B Bw4-80Ile was associated with delayed progression to AIDS [9] These data were supported by subsequent studies demonstrating enhanced function of KIR3DS1-expressing NK cells in HLA-B Bw4-80Ile(+) individuals and efficient in vitro suppression of HIV-1 replication in HLA-B Bw4-80Ile(+) target cells by KIR3DS1(+) NK cells [10,11]. Better control of HIV-1 viremia was described in individuals encoding for HLA-B
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