Viral Transmission in Organ Transplantation: The Importance of Risk Assessment

Organ transplantation presents a low but extant risk of allograft transmission of blood-borne viruses (BBV) including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Other infections temporarily present in blood are also transmissible from donor to recipient, such as cytomegalovirus (CMV), polyomavirus (BK), Epstein-Barr virus (EBV), and others, where the donor has acute infection at the time of donation. Decisions about accepting organs for transplantation involve a trade-off between the acquisition of good-quality organs, which can confer longer survival time for the recipient, but at the risk of dying from waiting too long from the underlying condition, versus accepting an organ of less quality, but at the risk of potentially acquiring a donor-derived infection (DDI), unless such infection can be ruled out in the donated organ. In this chapter, we describe the different factors contributing to the overall risk of acquiring a BBV infection through the allograft, mechanisms for assessing risk of the donor and the different strategies available to minimize or mitigate the risk. The process is one of risk assessments and risk ameliorations through optimum laboratory and clinical assessment processes, so that transplantation professionals can balance the overall risk against the life-saving and life-enhancing benefits of organ transplantation

Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies

Objective To review the association between current enterovirus infection diagnosed with molecular testing and development of autoimmunity or type 1 diabetes

Proficiency of Nucleic Acid Tests for Avian Influenza Viruses, Australasia

An avian influenza quality assurance program was used to provide information for laboratories on the sensitivity and specificity of their avian influenza nucleic acid testing. Most laboratories were able to correctly detect clinically relevant amounts of influenza virus (H5N1), and results improved as each subsequent panel was tested

Coxsackievirus B5 infection induces dysregulation of microRNAs predicted to target known type 1 diabetes risk genes in human pancreatic islets

Extensive research has identified enterovirus (EV) infections as key environmental triggers of type 1 diabetes. However, the underlying molecular mechanisms via which EVs contribute to the pathogenesis of type 1 diabetes remain unclear. Given that EVs dysregulate host microRNAs (miRNAs), which function as key regulators of β-cell biology, we investigated the impact of coxsackievirus B5 (CVB5) infection on the cellular expression of miRNAs within human islets. Using high-throughput quantitative PCR nanofluidics arrays, the expression of 754 miRNAs was examined in CVB5-infected human pancreatic islets. In total, 33 miRNAs were significantly dysregulated (≥ threefold difference) in the infected compared with control islets (P < 0.05). Subsequently, these differentially expressed miRNAs were predicted to target mRNAs of 57 known type 1 diabetes risk genes that collectively mediate various biological processes, including the regulation of cell proliferation, cytokine production, the innate immune response, and apoptosis. In conclusion, we report the first global miRNA expression profiling of CVB5-infected human pancreatic islets. We propose that EVs disrupt the miRNA-directed suppression of proinflammatory factors within β-cells, thereby resulting in an exacerbated antiviral immune response that promotes β-cell destruction and eventual type 1 diabetes

Incidence of primary hepatitis C infection and risk factors for transmission in an Australian prisoner cohort

Background. Hepatitis C virus (HCV) infection is common in prisoner populations, particularly those with a history of injecting drug use (IDU). Previous studies of HCV incidence have been based on small case numbers and have not distinguished risk event

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development

Cytomegalovirus pUL50 is the multi-interacting determinant of the core nuclear egress complex (NEC) that recruits cellular accessory NEC components

Nuclear egress of herpesvirus capsids through the nuclear envelope is mediated by the multimeric nuclear egress complex (NEC). The human cytomegalovirus (HCMV) core NEC is defined by an interaction between the membrane- anchored pUL50 and its nuclear co-factor pUL53, tightly associated through heterodimeric corecruitment to the nuclear envelope. Cellular proteins, such as p32/gC1qR, emerin and protein kinase C (PKC), are recruited by direct interaction with pUL50 for the multimeric extension of the NEC. As a functionally important event, the recruitment of both viral and cellular protein kinases leads to site- specific lamin phosphorylation and nuclear lamina disassembly. In this study, interaction domains within pUL50 for its binding partners were defined by co-immunoprecipitation. The interaction domain for pUL53 is located within the pUL50 N-terminus (residues 10-169), interaction domains for p32/gC1qR (100-358) and PKC (100-280) overlap in the central part of pUL50, and the interaction domain for emerin is located in the C-terminus (265-397). Moreover, expression and formation of core NEC proteins at the nuclear rim were consistently detected in cells permissive for productive HCMV replication, including two trophoblast-cell lines. Importantly, regular nuclear-rim formation of the core NEC was blocked by inhibition of cyclin-dependent kinase (CDK) activity. In relation to the recently published crystal structure of the HCMV core NEC, our findings result in a refined view of NEC assembly. In particular, we suggest that CDKs may play an important regulatory role in NEC formation during HCMV replica