HDAC Inhibitors as Epigenetic Regulators

Despite this thin rabbit-specific host range in nature, MYXV has proven to be capable of infecting a wide variety of human cancer cells in culture, and can selectively eliminate cancerous tissues for either xenografted human cancers in mice, or syngeneic murine cancers in rats and mice. elements of the rabbit innate and acquired immune responses. It has been documented that MYXV BIBX 1382 contamination rapidly leads to systemic immunosuppression in European rabbits. Depletion of lymphocytes in the draining lymph node has been reported as early as 24 hours after intradermal contamination of MYXV [2]. It has also been reported that upon MYXV contamination, all T cell subsets (CD4+, CD8+, and CD4+CD8+ T cells) decreased, while MYXVs effect on B cells was less pronounced [2]. In particular, the CD4+ T cell subpopulation was affected more severely compared to other T cell subsets. In addition, the ability of lymphocytes to proliferate was also compromised during the course of MYXV contamination [3]. This systemic MYXV-induced immunosuppression BIBX 1382 is utterly unique BIBX 1382 to infected European rabbits. In contrast, the virus is usually rapidly cleared by innate immune responses in all tested vertebrate hosts outside the lagomorph family of leporid hosts, including mice and humans. Thus, MYXV is considered a safe candidate oncolytic virus for potential human clinical trials. In addition, several of the targeted gene knockout constructs of MYXV, such as vMyx-M135KO and vMyx-M063KO, have lost the ability to be pathogenic even in rabbits while maintaining their oncolytic properties against human cancer cells, and thus represent newer-generation oncolytic candidate MYXV variants that are essentially avirulent for all those known vertebrate host species [4]. In recent years, MYXV has been shown to possess oncolytic activity in a variety of preclinical cancer models [5, 6]. Studies around the potential immunoregulatory properties of MYXV outside the rabbit host will lead to a better understanding of Igf1 the immune responses elicited by the host (particularly mouse or human) upon MYXV BIBX 1382 contamination and of their potential modulation in the animal models that are used to evaluate the therapeutic benefits of MYXV-based oncolytic treatments. Similar to the rest of the poxvirus family members, dozens of diverse immunoregulatory factors are encoded by MYXV [1]. In this review, we will focus on MYXV immunoregulatory factors with potential impacts on MYXV-based oncolytic applications as assessed in cellular or animal-based models (Table 1). Table 1 Immunoregulatory factors of myxoma virus M156 was shown to be an efficient substrate of PKR and to efficiently compete for phosphorylation with cellular eIF2. The VACV K3L protein and the swinepox C8L protein are also viral mimics of eIF2 and inhibitors of PKR [15, 16]. However the protein-protein interactions that lead to the inhibition of PKR by these three viral eIF2 mimics appear to be distinct and unique to each viral protein. Importantly, of the three eIF2 viral mimics tested to date only M156 has been reported to be phosphorylated upon binding to PKR [13]. Thus M156 may utilize a different mechanism of PKR inhibition when compared to C8L or K3L. Studies have also shown that this host may also in turn BIBX 1382 evolve to counteract viral mimicry. In a recent study, using the PKR-K3L model system, it was reported that PKR has evolved and undergone periods of strong positive selection in primates and that these evolutionary mechanisms may help overcome viral mimicry [17]. In fact, mutant PKR proteins have been identified that have decreased binding to K3L and therefore are resistant to its inhibitory effects, but yet still retain their binding affinity for eIF2 [18]. In the past years, the genomic sequences of naturally occurring strains of MYXV have been obtained. In Californian MYXV isolates, which are more virulent to European rabbits compared to South American strains, M156 has been found to be duplicated [19]. These findings support the prediction that M156 is usually a virulence factor for MYXV, and suggest that careful analysis of.