UL40-mediated NK evasion during productive infection with human cytomegalovirus

doi:10.1073/pnas.112680099

UL40-mediated NK evasion during productive infection with human cytomegalovirus

^*Section of Infection and Immunity, University of Wales College of Medicine, Tenovus Building, Heath Park, Cardiff CF14 4XX, United Kingdom; and ^§Medical Research Council Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom

Edited by Max D. Cooper, University of Alabama, Birmingham, AL, and approved April 9, 2002 (received for review December 18, 2001)

Abstract

Human cytomegalovirus (HCMV) exploits a range of strategies to evade and modulate the immune response. Its capacity to down-regulate MHC I expression was anticipated to render infected cells vulnerable to natural killer (NK) attack. Kinetic analysis revealed that during productive infection, HCMV strain AD169 first enhanced and then inhibited lysis of primary skin fibroblasts by a CD94/NKG2A⁺NKG2D⁺ILT2⁺ NK line. The inhibition of cytotoxicity against strain AD169-infected fibroblasts was abolished by prior treatment of targets or effectors with anti-MHC I and anti-CD94 monoclonal antibodies, respectively, implying a CD94/HLA-E-dependent mechanism. An HCMV strain AD169, UL40 deletion mutant could not inhibit CD94/NKG2A⁺ NK killing against skin fibroblasts. The contribution of UL40 to evasion of primary NK cells then was tested in a system where targets and effectors were MHC-matched. Primary NK cells activated with IFNα as well as cultured primary NK cell lines showed increased killing against ΔUL40-infected fibroblasts compared with AD169-infected targets. This effect was abrogated by depletion of CD94⁺ cells. These findings demonstrate that HCMV encodes a mechanism of evasion specifically targeted against a proportion of CD94⁺ NK cells and show that this system functions during a productive infection.

NK cells‖inhibition

Footnotes

↵ † E.C.Y.W. and B.M. contributed equally to this work.
↵ ‡ To whom reprint requests should be addressed. E-mail: wangec{at}cf.ac.uk.
↵ ¶ Present address: Sir Alexander Fleming Building, Imperial College Road, London SW7 2AZ, United Kingdom.
↵ ‖ Present address: Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, 06560 Valbonne, France.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

HCMV,

human cytomegalovirus;

NK,

natural killer;

KIR,

killer inhibitory receptor;

LIR,

leukocyte Ig-like receptor;

PBMC,

peripheral blood mononuclear cell;

EGFP,

enhanced green fluorescent protein;

MOI,

multiplicity of infection;

pi,

postinfection