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 . 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.
Human herpesviruses cause substantial morbidity and mortality. HSV-1 is regarded as one of the most common causes of viral encephalitis, an infection carrying significant risk of mortality [124
]. EBV, HCMV, and KSHV infections have the potential to not only cause severe manifestations during acute infection, but also the development of hematologic or solid malignancies [126
]. A variety of herpesviruses also cause cutaneous and ocular infections with potential for life-long morbidity [128
]. Thorough knowledge of specific viral immune evasion mechanisms may provide avenues for developing more effective therapies against disease related to human herpesviruses. Understanding NK cell evasion may improve oncolytic herpesvirus therapies for cancer [131
]. Insight into viral abilities to evade the immune system may also yield better markers for clinical prognosis and monitoring of active and latent infection [117
]. Continued research into these mechanisms of NK cell evasion will not only deepen basic understandings of human herpesviruses but may also serve to ultimately alleviate disease burden and guide strategies for clearance of persistent infection in immunocompromised patients.