The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing.

Einat Seidel,Corinna Schuler,Liat Dassa,Ofer Mandelboim,Dana G Wolf,Vu Thuy Khanh Le-Trilling,Esther Oiknine-Djian,Richard James Stanton

doi:10.1371/journal.ppat.1008807

Abstract

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.

Highlights

Human cytomegalovirus (HCMV) is a betaherpesvirus with a large double stranded DNA genome of approximately 235 kilo base pair [1]
Human cytomegalovirus (HCMV) is a common pathogen that usually causes asymptomatic infection in the immunocompetent population, but the immunosuppressed and fetuses infected in utero suffer mortality and disability due to HCMV disease
UL147A-deficient HCMV mutants are impaired in MICA 008 downregulation

Summary

Introduction

Human cytomegalovirus (HCMV) is a betaherpesvirus with a large double stranded DNA genome of approximately 235 kilo base pair (kbp) [1]. HCMV encodes 170 canonical genes and recent work has described noncanonical open reading frames, as well as several classes of small and large noncoding RNAs [2,3,4,5,6,7]. Infection with HCMV in healthy individuals is usually asymptomatic but results in lifetime persistence, due to HCMV’s remarkable ability to evade host immune responses [9]. The use of available drug treatments for HCMV is often limited by their significant toxicity [1], and though there are several promising candidates in development, no HCMV vaccine has been approved for use [11]. A better understanding of HCMV immune evasion mechanisms could aid in the development of novel treatments and vaccines that are urgently required [9]

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Conclusion