Varicella zoster virus (VZV) is the causative agent of chickenpox (varicella) and shingles (herpes zoster). VZV and other members of the herpesvirus family are distinguished by their ability to establish a latent infection, with the potential to reactivate and spread virus to other susceptible individuals. This lifelong relationship continually subjects VZV to the host immune system and as such VZV has evolved a plethora of strategies to evade and manipulate the immune response. This review will focus on our current understanding of the innate anti-viral control mechanisms faced by VZV. We will also discuss the diverse array of strategies employed by VZV to regulate these innate immune responses and highlight new knowledge on the interactions between VZV and human innate immune cells.

The nonclassical major histocompatibility complex (MHC) class I molecule HLA-E inhibits natural killer (NK) cell–mediated lysis by interacting with CD94/NKG2A receptors. Surface expression of HLA-E depends on binding of conserved peptides derived from MHC class I molecules. The same peptide is present in the leader sequence of the human cytomegalovirus (HCMV) glycoprotein UL40 (gpUL40). It is shown that, independently of the transporter associated with antigen processing, gpUL40 can up-regulate expression of HLA-E, which protects targets from NK cell lysis. While classical MHC class I molecules are down-regulated, HLA-E is up-regulated by HCMV. Induction of HLA-E surface expression by gpUL40 may represent an escape route for HCMV.

The genetic content of wild-type human cytomegalovirus was investigated by sequencing the 235 645 bp genome of a low passage strain (Merlin). Substantial regions of the genome (genes RL1–UL11, UL105–UL112 and UL120–UL150) were also sequenced in several other strains, including two that had not been passaged in cell culture. Comparative analyses, which employed the published genome sequence of a high passage strain (AD169), indicated that Merlin accurately reflects the wild-type complement of 165 genes, containing no obvious mutations other than a single nucleotide substitution that truncates gene UL128. A sizeable subset of genes exhibits unusually high variation between strains, and comprises many, but not all, of those that encode proteins known or predicted to be secreted or membrane-associated. In contrast to unpassaged strains, all of the passaged strains analysed have visibly disabling mutations in one or both of two groups of genes that may influence cell tropism. One comprises UL128, UL130 and UL131A, which putatively encode secreted proteins, and the other contains RL5A, RL13 and UL9, which are members of the RL11 glycoprotein gene family. The case in support of a lack of protein-coding potential in the region between UL105 and UL111A was also strengthened.

Human cytomegalovirus (HCMV) in clinical material cannot replicate efficiently in vitro until it has adapted by mutation. Consequently, wild-type HCMV differ fundamentally from the passaged strains used for research. To generate a genetically intact source of HCMV, we cloned strain Merlin into a self-excising BAC. The Merlin BAC clone had mutations in the RL13 gene and UL128 locus that were acquired during limited replication in vitro prior to cloning. The complete wild-type HCMV gene complement was reconstructed by reference to the original clinical sample. Characterization of viruses generated from repaired BACs revealed that RL13 efficiently repressed HCMV replication in multiple cell types; moreover, RL13 mutants rapidly and reproducibly emerged in transfectants. Virus also acquired mutations in genes UL128, UL130, or UL131A, which inhibited virus growth specifically in fibroblast cells in wild-type form. We further report that RL13 encodes a highly glycosylated virion envelope protein and thus has the potential to modulate tropism. To overcome rapid emergence of mutations in genetically intact HCMV, we developed a system in which RL13 and UL131A were conditionally repressed during virus propagation. This technological advance now permits studies to be undertaken with a clonal, characterized HCMV strain containing the complete wild-type gene complement and promises to enhance the clinical relevance of fundamental research on HCMV.

Human cytomegalovirus infection perturbs multiple cellular processes that could promote the release of proapoptotic stimuli. Consequently, it encodes mechanisms to prevent cell death during infection. Using rotenone, a potent inhibitor of the mitochondrial enzyme complex I (reduced nicotinamide adenine dinucleotide–ubiquinone oxido-reductase), we found that human cytomegalovirus infection protected cells from rotenone-induced apoptosis, a protection mediated by a 2.7-kilobase virally encoded RNA (β2.7). During infection, β2.7 RNA interacted with complex I and prevented the relocalization of the essential subunit genes associated with retinoid/interferon–induced mortality–19, in response to apoptotic stimuli. This interaction, which is important for stabilizing the mitochondrial membrane potential, resulted in continued adenosine triphosphate production, which is critical for the successful completion of the virus' life cycle. Complex I targeting by a viral RNA represents a refined strategy to modulate the metabolic viability of the infected host cell.