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  • The lack of robust immunocompetent animal models permissive


    The lack of robust immunocompetent animal models permissive for HCV makes it hard to assess if the quantity and quality of vaccine-induced immunity is sufficient to confer protection. Thus, it is difficult to predict to what extent antibody responses induced by current vaccination approaches, including those presented here, contribute to protection. In vivo, antibodies could facilitate protection independently of direct virus particle neutralization. For instance antibody dependent cytotoxicity may contribute to clearance of HCV infected cells. In this regard, binding but non-neutralizing antibodies may contribute to HCV protection, as has recently been reported for an HIV infection in vivo. Therefore, development of vaccination approaches inducing strong T cell responses as well as nNAbs and bNAbs and involving all antibody effector functions is likely of key importance for induction of robust protection.
    Financial support Twincore is a joint venture of Hannover Medical School and the Helmholtz-Centre for infection research. T.P. was supported by a grant from the DZIF (HCV-vaccine), and T.P. and C.A.G. were supported by the Helmholtz-Alberta Initiative for Infectious Disease Research (HAI-IDR).
    Conflict of interest Please refer to the accompanying ICMJE disclosure forms for further details.
    Authors’ contributions
    Introduction In conjunction with phosphorylation, ubiquitination process is one of the most studied post-translational modifications of proteins [1]. Ubiquitin is a protein of 76 Ac-Endothelin-1 (16-21), human which acts in sequence with three activating enzymes, known generically as UBE1, UBE2, UBE3 [2]. UBE1 enzyme forms an activated thiolester bond with ubiquitin, in an ATP-dependent reaction. For its part, UBE2 carries the activated ubiquitin from the UBE1-Ub complex to an UBE3 ubiquitin-ligase. The latter enzyme transfers the ubiquitin from the UBE2-Ub complex to a target protein or another ubiquitin. In general, UBE2 has the peculiarity of determining the type of ubiquitin chain assembled [3]. Therefore, UBE2 has a great relevance to determine the function of the ubiquitin chain, which is directly related with its structure, given by the different types of linkages that have been discovered [4]. Seven of the ubiquitin chain linkages, allowed by the connection between the UBE2 and UBE3 enzymes, involve internal lysines (K) that are linked to the carboxy-terminal diglycine of the consequent ubiquitin. Nevertheless, an eighth type of linkage was discovered, which is formed by an internal methionine of an ubiquitin with the carboxy-terminal carboxy group of the next one [5]. Previous studies have identified an association between the ubiquitination and the stimulation of genes cascades involved in the immune response. In this context, the up-regulation of genes involved in ubiquitination, such as UBE2, have related to increments in the activity of some key genes of the immune response like the cytokine TNF-α [6], [7], [8], [9]. Recently, the progress of the study of this process has revealed novel conformations of linear ubiquitin chains, which are two main components known as LUBAC (linear ubiquitin assembly chains) and SHAIRPIN (SHANK-associated RH domain interacting protein). Those conformations are unique because of the role of the UBE3 in determining the type of formation of the ubiquitin chain. Reports suggest the expression of genes involved in the innate immune response increase when ubiquitination follows this structure [4], [10]. These gene pathways are also activated in the absence of SHARPIN, even though gene transcription are significantly lower than those in the pathway with LUBAC activity [8]. In both cases, the role of UBE2 enzyme is crucial for the conformation of the structure that finally activates the transcription of immune-related genes. The immune response of various species has been studied under different approaches. One approach is to identify punctual polymorphism (SNPs) in candidate genes involved in immune response. It is previously reported that SNPs in these genes could alter the conformation of some genes, and therefore influence in the resistance/susceptibility of organisms to diseases [11]. Thousands of SNPs markers related to immune response genes have been discovered in different aquatic species, such as rainbow trout, oyster, turbot and common carps [12], [13], [14], [15]. Additionally, an SNP in the serine protease inhibitor gene of the eastern oyster was associated with resistance/susceptibility to bacterial disease [16]. Numerous studies have evaluated the transcription patterns of candidate genes involved in innate immune response of marine species and have associated these patterns to the response to pathogens [17], [18], [19], [20], [21], [22], [23], [24]. However, until now there have been no reports that associate SNP markers and its influence on the gene transcription pattern of candidate genes.