Skip Navigation LinksHome > June 19, 2014 - Volume 28 - Issue 10 > Sequence variations in HIV-1 p24 Gag-derived epitopes can al...
doi: 10.1097/QAD.0000000000000284
Basic Science

Sequence variations in HIV-1 p24 Gag-derived epitopes can alter binding of KIR2DL2 to HLA-C*03: 04 and modulate primary natural killer cell function

van Teijlingen, Nienke H.a,b,*; Hölzemer, Angeliquea,*; Körner, Christiana; García-Beltrán, Wilfredo F.a; Schafer, Jamie L.c,d; Fadda, Lenaa; Suscovich, Todd J.a; Brander, Christiane; Carrington, Marya,f; Evans, David T.c,d,g; van Baarle, Debbieh,i; Altfeld, Marcusa,j

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Objective: The aim of this study was to assess the consequence of sequence variations in HLA-C*03:04-presented HIV-1 p24 Gag epitopes on binding of the inhibitory natural killer (NK) cell receptor KIR2DL2 to HLA-C*03:04.

Design: HIV-1 may possibly evade recognition by KIR+ NK cells through selection of sequence variants that interfere with the interactions of inhibitory killer cell immunoglobulin-like receptors (KIRs) and their target ligands on HIV-1 infected cells. KIR2DL2 is an inhibitory NK cell receptor that binds to a family of HLA-C ligands. Here, we investigated whether HIV-1 encodes for HLA-C*03:04-restricted epitopes that alter KIR2DL2 binding.

Methods: Tapasin-deficient 721.220 cells expressing HLA-C*03:04 were pulsed with overlapping peptides (10mers overlapped by nine amino acids, spanning the entire HIV-1 p24 Gag sequence) to identify peptides that stabilized HLA-C expression. The impact that sequence variation in HLA-C*03:04-binding HIV-1 epitopes has on KIR2DL2 binding and KIR2DL2+ NK cell function was determined using KIR2DL2-Fc constructs and NK cell degranulation assays.

Results: Several novel HLA-C*03:04 binding epitopes were identified within the HIV-1 p24 Gag consensus sequence. Three of these consensus sequence peptides (Gag144–152, Gag163–171 and Gag295–304) enabled binding of KIR2DL2 to HLA-C*03:04 and resulted in inhibition of KIR2DL2+ primary NK cells. Furthermore, naturally occurring minor variants of epitope Gag295–304 enhanced KIR2DL2 binding to HLA-C*03:04.

Conclusion: Our data show that naturally occurring sequence variations within HLA-C*03:04-restricted HIV-1 p24 Gag epitopes can have a significant impact on the binding of inhibitory KIR receptors and primary NK cell function.

© 2014 Lippincott Williams & Wilkins, Inc.


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