Of the inactivated and subunit vaccines, the candidate that is most advanced in clinical trials is a self-replicating RNA-based vaccine containing six mRNAs coding for the components of the pentameric complex and gB. NK immune evasion genes encoded by HCMV aimed at subverting the NK cell immune response. As such, ongoing studies that have utilized HCMV to investigate NK cell diversity and function have proven instructive. Here, we discuss our current understanding of NK cell memory to viral infection with a focus on the response to cytomegaloviruses. We will then discuss the implications that this will have for the development of a vaccine against HCMV with particular emphasis on how a strategy that can harness the innate immune system and NK cells could be crucial for the development of a vaccine against this high-priority pathogen. dissociation [68].NKG2DMICA/BUL16, UL142, UL148A, US9, US18, US20, miR-UL112UL16, UL142- intracellular retention [88,89]; UL148A, US18, US20- lysosomal degradation [87,90]; US9- proteasomal degradation (MICA*008) [69], miR-UL112- downregulation of MICB expression [91].-ULBPsUL16, UL142, US12, US13, US20UL16, UL142- intracellular retention [88,92,93]; US20- lysosomal degradation [87]; US12, US13- downregulation of ULBPs [94].DNAM-1CD112UL141 (requires US2)ER retention [95].-CD155UL141ER retention [96].TACTILECD111—CD155UL141ER retention [96].2B4CD48–CD2LFA-3UL148Lysosomal degradation [97].CD16Fc of IgGRL11-13, UL119-UL118Fcbinding and inhibition of Fc receptor signalling, inhibition of ADCC [98].TRAILTRAIL-R1/-R2UL141ER retention [99].CD45pUL11pUL11Inhibition of CD45 mediated signalling through direct binding of pUL11 [100].InhibitoryInhibitory KIRMHC-I polymorphisms–LIR-1MHC-IaUL18MHC-I homolog [101].CD94-NKG2A/BHLA-EUL40UL40 encodes a TAP-independent signal peptide that stabilises HLA-E surface expression [85].TACTILECD111—CD155UL141ER retention [96].TIGIT/ PVRIGCD112UL141 (requires US2)ER retention [95].-CD155UL141ER retention [96].CadherinsKLRG1–LLT1CD161 (NKR-P1A—WAVE2/F-actinUL135Suppression of immune synapse formation [102]. Open in a separate window BAT3: HLA-B associated transcript 3; DNAM-1: DNAX accessory molecule-1; HLA: human leukocyte antigen; KIR: killer-cell immunoglobulin-like receptors; KLRG1: killer cell lectin-like receptor subfamily G member 1; LFA3: lymphocyte function-associated antigen 3 (CD58); LIR: leukocyte immunoglobulin-like receptor; LLT1: lectin-like transcript-1 (CLEC2D); MICA/B: MHC class I polypeptideCrelated sequence A/B; miR: microRNA; NKR-P1: natural killer cell receptor protein 1 (KLRB1-killer cell lectin-like receptor subfamily B, member 1, CD161); PVRIG: poliovirus receptor related immunoglobulin domain containing; TACTILE: T cell activation, increased late expression (CD96); TIGIT: T cell immunoreceptor with Ig and ITIM domains; TRAIL: TNF-related apoptosis-inducing ligand; ULBP: UL16 binding protein; US/L: unique short/long; WAVE2: Wiskott-Aldrich syndrome protein family member 2. Viral infection also induces cellular stress that could result in upregulation of stress ligands recognized by Cisplatin NK cell activating receptors. Such stress ligands include the UL16 binding proteins (ULBPs), the MHC-I polypeptide-related sequence A/B (MICA/B), nectin and nectin-like proteins (CD112, CD155), CD48 and CD58 [53,58,61,62,63,64,65]. These stress-induced molecules are recognized by the activating receptors NKG2D, DNAM-1, 2B4 and CD2 with NK cell activation typically requiring signaling through more than one of these Cisplatin receptors [66,67]. HCMV counters these stress responses by encoding proteins that downregulate stress-induced ligands on infected cells and in some cases also directly target the corresponding activating receptor [58,68]. However, the dynamic relationship between Cisplatin virus and host is demonstrated by the presence of the highly prevalent MICA*008 allele in humans that appears to have been positively selected. This allele acquired a frameshift mutation to escape downregulation by HCMV UL142, but in response, HCMV has evolved the US9 protein, which targets this escape variant highlighting the adaptability of the virus [69]. Other activating receptors targeted by HCMV include the natural cytotoxicity receptor NKp30, with the viral protein pp65 causing dissociation of the receptor from one of its adaptor molecules, CD3 [68]. NK cells can also target virally-infected cells by ADCC through the expression of Rabbit polyclonal to IL9 FcRIII (CD16) that recognizes the Fc portions of IgG. Signaling through FcRIII alone is sufficient for NK cell activation and cytotoxicity. HCMV encodes several immune evasion molecules that bind the Fc chain of IgG and thus prevent activation of NK cells through FcRIII [66]. 5. HCMV Vaccination: Current Strategies The first HCMV vaccine candidates were live attenuated viruses with the laboratory strains AD169 [70] and Towne [71] as vaccines. AD169 was soon dropped from trials due to low efficacy. The Towne strain conferred protection against challenge with a non-attenuated strain but failed to prevent acquisition in later trials and was not taken forward [72]. The next candidates were based on purified recombinant viral glycoproteins, predominantly glycoprotein B (gB) because of its key function in cell-entry and infection [73]. The major immunization studies with gB have given it in combination with different adjuvants, most notably MF59 and AS01 that had been extensively tested in a number of human and animal trials. The gB/MF59 vaccine offered partial protection, eliciting anti-gB antibodies and reducing HCMV acquisition in two phase II trials [74,75] and reducing virologic parameters in HCMV-negative transplant patients who received an organ from an HCMV-positive donor [76]. The gB AS01 vaccine formulation has shown promising results in guinea pig models of CMV congenital infection [77] and robust antibody response with evidence of virus neutralization in a phase I study in humans [78]. However, no further results have been published and the vaccine did not proceed to further testing. Although gB/MF59 did not reach significant efficacy to support recommendation and licensure,.