HIV-1-Mediated Downmodulation of HLA-C Impacts Target Cell Recognition and Antiviral Activity of NK Cells

Publication date: 12 July 2017
Source:Cell Host & Microbe, Volume 22, Issue 1
Author(s): Christian Körner, Camille R. Simoneau, Philipp Schommers, Mitchell Granoff, Maja Ziegler, Angelique Hölzemer, Sebastian Lunemann, Janet Chukwukelu, Björn Corleis, Vivek Naranbhai, Douglas S. Kwon, Eileen P. Scully, Stephanie Jost, Frank Kirchhoff, Mary Carrington, Marcus Altfeld
It was widely accepted that HIV-1 downregulates HLA-A/B to avoid CTL recognition while leaving HLA-C unaltered in order to prevent NK cell activation by engaging inhibitory NK cell receptors, but it was recently observed that most primary isolates of HIV-1 can mediate HLA-C downmodulation. Now we report that HIV-1-mediated downmodulation of HLA-C was associated with reduced binding to its respective inhibitory receptors. Despite this, HLA-C-licensed NK cells displayed reduced antiviral activity compared to their unlicensed counterparts, potentially due to residual binding to the respective inhibitory receptors. Nevertheless, NK cells were able to sense alterations of HLA-C expression demonstrated by increased antiviral activity when exposed to viral strains with differential abilities to downmodulate HLA-C. These results suggest that the capability of HLA-C-licensed NK cells to control HIV-1 replication is determined by the strength of KIR/HLA-C interactions and is thus dependent on both host genetics and the extent of virus-mediated HLA-C downregulation.

Graphical abstract

Teaser

HIV-1 modulates the expression of ligands for receptors expressed by natural killer (NK) cells on infected cells to evade NK cell recognition. Körner et al. demonstrate that NK cells are able to sense HIV-1-mediated downmodulation of HLA-C through decreased binding of inhibitory KIR receptors to HLA-C.


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