期刊
AIDS
卷 28, 期 10, 页码 1399-1408出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0000000000000284
关键词
HIV-1 epitopes; innate immunity; killer cell immunoglobulin-like receptor; natural killer cell
资金
- Doris Duke Charitable Foundation
- Ragon Institute of MGH, MIT and Harvard
- NIH [R01 AI066031, P30 AI060354, R01 AI095098]
- Frederick National Laboratory for Cancer Research [HHSN261200800001E]
- NIH (Frederick National Lab, Center for Cancer Research)
- Harvard University Center for AIDS Research (CFAR)
- NIH, NIAID
- NIH, NCI
- NIH, NICHD
- NIH, NHLBI
- NIH, NIDA
- NIH, NIMH
- NIH, NIA
- NIH, NCCAM
- NIH, FIC
- NIH, OAR
- Huygens Scholarship Programme
- German Academic Exchange (DAAD) scholarship
- Koln Fortune Programme
- Ragon Fellowship of the Ragon Institute of MGH, MIT and Harvard
- ICREA Funding Source: Custom
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. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
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