Impact of direct-acting antiviral treatment for hepatitis C on cardiovascular diseases and extrahepatic cancers.

PURPOSE: The impact of direct-acting antivirals (DAAs) on extrahepatic complications in chronic hepatitis C (CHC) patients remains poorly described. We estimated the association of DAAs with cardiovascular events and extrahepatic cancers. METHODS: The prospective ANRS CO22 HEPATHER cohort was enriched with individual data until December 2018 from the French Health Insurance Database (SNDS). CHC patients were enrolled between August 2012 and December 2015 in 32 French hepatology centers. A total of 8148 CHC adults were selected. Cardiovascular events (stroke, acute coronary syndrome, pulmonary embolism, heart failure, arrhythmias and conduction disorders [ACD], peripheral arterial disease [PAD]) and extrahepatic solid cancers were derived from the SNDS. Associations between DAAs and extrahepatic events were estimated using marginal structural models, with adjustments for clinical confounders. RESULTS: Analyses of 12 905 person-years of no DAA exposure and 22 326 person-years following DAA exposure showed a decreased risk of PAD after DAA exposure (hazard ratio [HR], 0.54; 95% CI, 0.33-0.89), a beneficial effect of DAAs on overall cardiovascular outcomes in patients with advanced fibrosis (aHR, 0.58; 95% CI, 0.42-0.79), and an increased risk of ACD (hazard ratio [HR], 1.46; 95% CI, 1.04-2.04), predominant after the first year following DAA initiation. There was no association between DAAs and extrahepatic cancer risk (HR, 1.23; 95% CI, 0.50-3.03). CONCLUSIONS: DAAs were not associated with extrahepatic cancer development or reduction. They were associated with a decreased risk of PAD and an increased risk of ACD, supporting long-term cardiac monitoring after DAA therapy.

The CREB3-Herp signalling module limits the cytosolic calcium concentration increase and apoptosis induced by poliovirus.

Poliovirus (PV)-induced apoptosis seems to play a major role in central nervous system (CNS) tissue injury, a crucial feature of the pathogenesis of poliomyelitis. We have previously shown that calcium (Ca2+) flux from the endoplasmic reticulum (ER) to the cytosol during PV infection is involved in apoptosis induction in human neuroblastoma cells. We show here that PV infection is associated with a transient upregulation of Herp (homocysteine-induced ER protein), a protein known to promote the degradation of ER-resident Ca2+ channels. Herp gene transcription is controlled by the transcription factor CREB3 (cAMP response element-binding protein 3). We found that the CREB3/Herp pathway limited the increase in cytosolic Ca2+ concentration and apoptosis early in PV infection. This may reduce the extent of PV-induced damage to the CNS during poliomyelitis.

The Golgi protein ACBD3, an interactor for poliovirus protein 3A, modulates poliovirus replication.

We have shown that the circulating vaccine-derived polioviruses responsible for poliomyelitis outbreaks in Madagascar have recombinant genomes composed of sequences encoding capsid proteins derived from poliovaccine Sabin, mostly type 2 (PVS2), and sequences encoding nonstructural proteins derived from other human enteroviruses. Interestingly, almost all of these recombinant genomes encode a nonstructural 3A protein related to that of field coxsackievirus A17 (CV-A17) strains. Here, we investigated the repercussions of this exchange, by assessing the role of the 3A proteins of PVS2 and CV-A17 and their putative cellular partners in viral replication. We found that the Golgi protein acyl-coenzyme A binding domain-containing 3 (ACBD3), recently identified as an interactor for the 3A proteins of several picornaviruses, interacts with the 3A proteins of PVS2 and CV-A17 at viral RNA replication sites, in human neuroblastoma cells infected with either PVS2 or a PVS2 recombinant encoding a 3A protein from CV-A17 [PVS2-3A(CV-A17)]. The small interfering RNA-mediated downregulation of ACBD3 significantly increased the growth of both viruses, suggesting that ACBD3 slowed viral replication. This was confirmed with replicons. Furthermore, PVS2-3A(CV-A17) was more resistant to the replication-inhibiting effect of ACBD3 than the PVS2 strain, and the amino acid in position 12 of 3A was involved in modulating the sensitivity of viral replication to ACBD3. Overall, our results indicate that exchanges of nonstructural proteins can modify the relationships between enterovirus recombinants and cellular interactors and may thus be one of the factors favoring their emergence.

Recrutement des kinases PI4KIII aux organelles de réplication virale au cours de l'infection par le poliovirus et d'autres virus à ARN de polarité positive.

One characteristic of infections with RNA viruses of positive polarity is the generation of new specialized membrane structures acting as platforms accommodating the complexes involved in replication of the viral genome. The functionality of these "replication organelles" is dependent on interactions between viral nonstructural proteins, recruited host factors and viral RNAs. Poliovirus, the causal agent of paralytic poliomyelitis, is the model most frequently used for identification of the viral and cellular components involved in this process. Several recent studies have suggested that the efficiency of genome replication for poliovirus and other members of the Picornaviridæ family results from the recruitment of a phosphatidylinositol (PI) kinase, PI4KIIIß (phosphatidylinositol-4-kinase IIIß), which generates a lipid membrane microenvironment rich in PI4P (phosphatidylinositol-4-phosphate) at sites of replication. The nonstructural protein 3A of these viruses has been shown to play a role in the enrichment of replication organelle membranes in PI4KIIIß, but the mechanisms of kinase recruitment seem to differ between members of this family of viruses. Hepatitis C, from the Flaviviridæ family, recruits another PI4KIII kinase, PI4KIIIα, to sites of replication, through another nonstructural protein, NS5A. In this review, we will describe the various recently proposed models and the potential role of PI4P lipids. Finally, we will show that PI4KIII kinases are potential targets for the development of antiviral drugs targeting many positive-polarity RNA viruses.

Calcium flux between the endoplasmic reticulum and mitochondrion contributes to poliovirus-induced apoptosis.

We show that poliovirus (PV) infection induces an increase in cytosolic calcium (Ca(2+)) concentration in neuroblastoma IMR5 cells, at least partly through Ca(2+) release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP(3)R) and ryanodine receptor (RyR) channels. This leads to Ca(2+) accumulation in mitochondria through the mitochondrial Ca(2+) uniporter and the voltage-dependent anion channel (VDAC). This increase in mitochondrial Ca(2+) concentration in PV-infected cells leads to mitochondrial dysfunction and apoptosis.