Cytokine signaling from IL-15 is critical for the development of NK cells and is required throughout their lifetime. replication and dissemination, and a poor NK cell response may predispose an individual to chronic viral infections. Both HHV-6A and HHV-6B can interfere with NK cell-mediated anti-viral responses but the mechanisms by which each of these viruses impact NK cell activity differs. In this review, we will explore the nuanced associations between the two viruses and NK cells, discussing, in addition, relevant disease associations. order, family, subfamily, and genus. HHV-6 is usually classified into HHV-6A and HHV-6B as two unique species [1]. The term HHV-6 remains in usage and collectively refers to the two species. HHV-6 exhibits wide cell tropism in vivo and, as with other herpesviruses, induces a lifelong latent contamination in humans (Table 1). HHV-6 preferentially replicates in activated CD4+ T lymphocytes [2,3] and uses specific cell receptors permitting computer virus anchorage to the cell surface: HHV-6A uses CD46, a regulator of match activation expressed on all nucleated cells, while CD134 (also called OX40), a member of the tumor necrosis factor (TNF) receptor superfamily present only on activated T lymphocytes, functions as a specific access receptor for HHV-6B [4,5]. In addition to CD4+ T lymphocytes, HHV-6 can infect in vitro CD8+ T lymphocytes (only with HHV-6A), human fibroblasts, natural killer (NK) cells, liver cells, epithelial cells, endothelial cells, astrocytes, oligodendrocytes, and microglial cells [2,6,7,8,9,10,11,12,13]. The host tissue range of HHV-6 in vivo appears to be broader than might be expected from in vitro studies and includes the brain, tonsils, salivary glands, kidneys, liver, lymph nodes, heart, lungs, gastrointestinal RAC tract, and monocytes/macrophages [2,14,15,16]. The preferential sites for computer virus latency are suspected to be monocytes/macrphages, bone marrow progenitors and central nervous system (CNS) cells [17,18,19]. Table 1 HHV-6A and HHV-6B host-interaction characteristics. gene, binds to the origin of lytic replication (ori-lyt) and denatures a portion of the circular viral DNA genome [47]. This space is Aprepitant (MK-0869) maintained by the helicase/primase complex, consisting of the and gene products, which also provides RNA primers for the lagging-strand DNA synthesis [48]. The single-stranded DNA in the replication bubble is usually stabilized by the major DNA binding protein, encoded by and genes of HHV-6 are suspected of being involved in DNA replication as well, although their functions are not yet comprehended [51]. As the new strand develops, the circular replication structure is usually nicked to form a rolling circle intermediate. Long concatameric strands of progeny DNA are encapsidated by the conversation of cleavage and packaging proteins with specific packaging (pac) signals at the end of the viral genomes. Notably, ori-lyt and pac sequences are different for HHV-6A and HHV-6B [52]. The mature capsids bud out of the nucleus (thereby temporarily acquiring an intermediate membrane devoid of glycoproteins) into the cytoplasm, where they acquire a tegument and a secondary spiked viral envelope at the Golgi complex or at annulate lamellae, Aprepitant (MK-0869) where viral glycoproteins accumulate. These are sequentially glycosylated in transport vesicles prior to the release of mature computer virus particles into the extracellular space by exocytosis. The HHV-6 maturation pathway is different from that of the other herpesviruses in Aprepitant (MK-0869) that no viral glycoproteins are detectable in the cell membrane of infected cells [53]. The total time from contamination to release of new virions takes approximately 72 h. Like the other human herpesviruses, HHV-6 is usually capable of persisting in the host after primary contamination, and nonproductive contamination is characterized by the presence of latency-associated transcripts [54]. The gene product, the expression of which has impaired the migration of endothelial cells [5] and human oligodendrocyte progenitor cells in vitro [55], may enable the establishment and/or maintenance of latent contamination [56]. Although HHV-6 has primarily been analyzed in cases of acute productive contamination, as in instances of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) and reactivation in solid organ and HSCT recipients, the ability of the computer virus to induce changes in its environment in the absence of strong episodes of replication [57,58] has spurred growing desire for chronic, semi-latent HHV-6 infections. As HHV-6 is able to infect a great.