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

Nienke H. Van Teijlingen, Angelique Hölzemer, Christian Körner, Wilfredo F. García-Beltrán, Jamie L. Schafer, Lena Fadda, Todd J. Suscovich, Christian Brander, Mary Carrington, David T. Evans, Debbie Van Baarle, Marcus Altfeld

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

OBJECTIVE:: The aim of this study was to assess the consequence of sequence variations in HLA-C03:04-presented HIV-1 p24 Gag epitopes on binding of the inhibitory natural killer (NK) cell receptor KIR2DL2 to HLA-C03:04. 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-C03:04-restricted epitopes that alter KIR2DL2 binding. METHODS:: Tapasin-deficient 721.220 cells expressing HLA-C03:04 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-C03:04-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-C03:04 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-C03:04 and resulted in inhibition of KIR2DL2+ primary NK cells. Furthermore, naturally occurring minor variants of epitope Gag295-304 enhanced KIR2DL2 binding to HLA-C03:04. CONCLUSION:: Our data show that naturally occurring sequence variations within HLA-C03:04-restricted HIV-1 p24 Gag epitopes can have a significant impact on the binding of inhibitory KIR receptors and primary NK cell function. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Original languageEnglish
Pages (from-to)1399-1408
JournalAIDS
Volume28
Issue number10
DOIs
Publication statusPublished - 19 Jun 2014

Keywords

  • HIV-1 epitopes
  • Innate immunity
  • Killer cell immunoglobulin-like receptor
  • Natural killer cell

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this