Abstract
Human cytomegalovirus (HCMV) is an important pathogen that infects the majority of the population worldwide, yet, currently, there is no licensed vaccine. Despite HCMV encoding at least seven Natural Killer (NK) cell evasion genes, NK cells remain critical for the control of infection in vivo. Classically Antibody-Dependent Cellular Cytotoxicity (ADCC) is mediated by CD16, which is found on the surface of the NK cell in a complex with FcεRI-γ chains and/or CD3ζ chains. Ninety percent of NK cells express the Fc receptor CD16; thus, they have the potential to initiate ADCC. HCMV has a profound effect on the NK cell repertoire, such that up to 10-fold expansions of NKG2C+ cells can be seen in HCMV seropositive individuals. These NKG2C+ cells are reported to be FcεRI-γ deficient and possess variable levels of CD16+, yet have striking ADCC functions. A subset of HCMV cell surface proteins will induce robust antibody responses that could render cells susceptible to ADCC. We will consider how the strong anti-HCMV function of NKG2C+ FcεRI-γ-deficient NK cells could potentially be harnessed in the clinic to treat patients suffering from HCMV disease and in the development of an efficacious HCMV vaccine.
Highlights
Human cytomegalovirus (HCMV), the prototype member of the β-herpesvirus family, establishes lifelong infections in immunocompetent individuals, which only rarely results in overt disease.in certain populations, HCMV is a major cause of clinical problems
Patients suffering from reduced Natural Killer (NK) cell numbers as a result of Absolute NK Cell Deficiency (ANKD) or because of unknown aetiology are reported to suffer from recurrent HCMV infections and potentially life-threatening HCMV disease [15,19,20,21]
NK cells express activating and inhibitory receptors on their surface, and it is the balance of these signals, brought about by interaction with ligands, that determines the NK cell’s response; if the NK cell receives an overall inhibitory signal, it will leave a potential target cell intact; if the overall signal is activatory, it will set in motion a cascade of events that lead to the death of the target cell [50]
Summary
Human cytomegalovirus (HCMV), the prototype member of the β-herpesvirus family, establishes lifelong infections in immunocompetent individuals, which only rarely results in overt disease. Healthy HCMV seropositive individuals have large clonal expansions of CD8+ T-cells, and bone marrow transplantation studies demonstrate a strong correlation between the recovery of the CD8+ T-cell population and protection from HCMV disease [6,7,8,9,10]. It has been known for some time that HCMV has profound effects on the NK cell repertoire: expansions of NK cells expressing the activating lectin-like receptor, CD94-NKG2C, are readily detectable in a large proportion of HCMV seropositive individuals [23].
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