HLA-Cw*0102-Restricted HIV-1 p24 Epitope Variants Can Modulate the Binding of the Inhibitory KIR2DL2 Receptor and Primary NK Cell Function

被引：57

作者：

Fadda, Lena ^{[1
]}

Koerner, Christian ^{[1
]}

Kumar, Swati ^{[1
]}

Van Teijlingen, Nienke H. ^{[1
]}

Piechocka-Trocha, Alicja ^{[1
]}

Carrington, Mary ^{[1
,2
]}

Altfeld, Marcus ^{[1
]}

机构：

[1] Ragon Inst MGH MIT & Harvard, Charlestown, MA USA

[2] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA

来源：

PLOS PATHOGENS | 2012年 / 8卷 / 07期

关键词：

MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTOR; VIRUS TYPE-1 INFECTION; NATURAL-KILLER-CELLS; COMPLEX CLASS-I; HLA-B; PEPTIDE BINDING; CRYSTAL-STRUCTURE; CUTTING EDGE; RECOGNITION;

D O I：

10.1371/journal.ppat.1002805

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 Gag(209-218) AAEWDRLHPV) allowed for binding of KIR2DL2. Notably, functional analysis showed a significant inhibition of KIR2DL2(+) NK cells in the presence of p24 Gag(209-21)8-pulsed T2 cells, while degranulation of KIR2DL2(2) 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 Gag(209-218)) 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.

引用

页数：9