Research Article: Human Herpesviridae Methods of Natural Killer Cell Evasion

Date Published: July 8, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Carl I. Odom, David C. Gaston, James M. Markert, Kevin A. Cassady.


Human herpesviruses cause diseases of considerable morbidity and mortality, ranging from encephalitis to hematologic malignancies. As evidence emerges about the role of innate immunity and natural killer (NK) cells in the control of herpesvirus infection, evidence of viral methods of innate immune evasion grows as well. These methods include interference with the ligands on infected cell surfaces that bind NK cell activating or inhibitory receptors. This paper summarizes the most extensively studied NK cell receptor/ligand pairs and then describes the methods of NK cell evasion used by all eight herpesviruses through these receptors and ligands. Although great strides have been made in elucidating their mechanisms, there is still a disparity between viruses in the amount of knowledge regarding innate immune evasion. Further research of herpesvirus innate immune evasion can provide insight for circumventing viral mechanisms in future therapies.

Partial Text

The human herpes family of viruses includes human cytomegalovirus (HCMV), Kaposi’s sarcoma herpesvirus (KSHV), herpes simplex virus types 1 and 2 (HSV-1, 2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), and human herpesvirus 6 and 7 (HHV6, 7). These viruses share similar characteristics: all contain linear double-stranded DNA, are enveloped, and undergo latent and lytic lifecycles. However, there are important differences between these viruses in terms of infection niche and immune evasion strategies for persistent infection.

NK cells are important innate immune cells involved in the regulation of viral infection [14, 15]. They are a lymphocyte subset of the innate immune system that kills without prior exposure and sensitization to antigens via release of granzymes, perforin, TRAIL, and FAS ligand [16]. NK cells are regulated through surface receptor interactions with ligands expressed on stressed cells, such as virally infected or malignantly transformed cells. NK cells possess both activating and inhibitory cell surface receptors; it is the balance of ligand interactions with these receptors that determine NK cell activation. The structures, functions, and signaling mechanisms of these receptors and their ligands are comprehensively reviewed in references [16–21]. In addition to receptor-mediated regulation, cytokines induced during viral infection (IL-15, IL-12, IL-8, IFN-α, and IFN-β) can indirectly activate NK cells as well [6]. A summary of the receptors present on NK cells and associated ligands most relevant to immune evasion by human herpesviruses is provided below.

Human herpesviruses have evolved multiple mechanisms to dampen NK cell cytotoxicity, interacting with many of the factors influencing the balance of NK cell activation and inhibition. A summary of these mechanisms is provided in Table 1. A number of methods employed by human herpesviruses hinder the expression of NK cell ligands on infected cells. This method of immune evasion has been studied in different members of the herpesvirus family, defining marked similarities and stark differences between family members. Multiple mechanisms offset the indirect NK cell activation prompted by lack of MHC-I surface expression. As many human herpesviruses diminish MHC-I presentation of viral antigens to avoid detection by cytotoxic T lymphocytes, these mechanisms may offset the loss of NK cell inhibition from “Missing Self” [64, 67].

Human herpesviruses possess multiple mechanisms for evading both innate and adaptive immune responses. A summary of NK cell receptors, their ligands, and viral mechanisms interfering with each is provided in Table 1. A primary point of interest is the diversity of NK cell evasion mechanisms employed by human herpesviruses. Other than mechanisms shared by the highly similar HSV-1 and HSV-2, the human herpesviruses have evolved different mechanisms for subverting the immune response. It is also notable that these immunoevasion mechanisms do not group with herpesvirus subfamilies. For example, HCMV (a betaherpesvirus) and KSHV (a gammaherpesvirus) both encode microRNA’s targeting MICB yet downmodulate MICA via different mechanisms. The NK cell evasion mechanisms are unique to each human herpesvirus likely reflecting selection pressures encountered in the various infection niches occupied by the viruses. The lack of well-defined mechanisms of NK cell immunoevasion by given herpesviruses (i.e., HSV and VZV) is puzzling. There is well-documented persistence of HSV in patients with NK cell defects and the importance of NK cell involvement in the control of disease. Continuing research will likely reveal as yet unknown mechanisms of immunoevasion by the alpha herpesviruses.