Disarming Cellular Alarm Systems-Manipulation of Stress-Induced NKG2D Ligands by Human Herpesviruses

Abstract

The coevolution of viruses and their hosts led to the repeated emergence of cellular alert signals and viral strategies to counteract them. The herpesvirus family of viruses displays the most sophisticated repertoire of immune escape mechanisms enabling infected cells to evade immune recognition and thereby maintain infection. The herpesvirus family consists of nine viruses that are capable of infecting humans: herpes simplex virus 1 and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), roseoloviruses (HHV-6A, HHV-6B, and HHV-7), and Kaposi's-sarcoma-associated herpesvirus (KSHV). Most of these viruses are highly prevalent and infect a vast majority of the human population worldwide. Notably, research over the past 15 years has revealed that cellular ligands for the activating receptor natural-killer group 2, member D (NKG2D)-which is primarily expressed on natural killer (NK) cells-are common targets suppressed during viral infection, i.e., their surface expression is reduced in virtually all lytic herpesvirus infections by diverse mechanisms. Here, we review the viral mechanisms by which all herpesviruses known to date to downmodulate the expression of the NKG2D ligands. Also, in light of recent findings, we speculate about the importance of the emergence of eight different NKG2D ligands in humans and further allelic diversification during host and virus coevolution.

Keywords: NKG2D; NKG2D ligands; coevolution; herpesvirus; host-pathogen interaction; immune evasion; stress-induced ligands.

Figure 1

The human genome encodes for eight functional stress-induced ligands, subdivided in the MIC and ULBP family. MICA, MICB, ULBP4, and ULBP5 contain a transmembrane domain, whereas ULBP1, 2, and 3 and one particular allele of MICA, MICA*008, are GPI-anchored. Interestingly, MICA and MICB, genes having a high evolutionary plasticity as reflected by the number of allelic variants, seem to be targeted more frequently by viral immune evasion mechanisms.