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Sickle cell disease (SCD) is an inherited blood disorder characterized by sickled red blood cells (RBCs), which are more sensitive to haemolysis and can contribute to disease pathophysiology. Although treatment of SCD can include RBC transfusion, patients with SCD have high rates of alloimmunization. We hypothesized that RBCs from patients with SCD have functionally active mitochondria and can elicit a type 1 interferon response. We evaluated blood samples from more than 100 patients with SCD and found elevated frequencies of mitochondria in reticulocytes and mature RBCs, as compared to healthy blood donors. The presence of mitochondria in mature RBCs was confirmed by flow cytometry, electron microscopy, and proteomic analysis. The mitochondria in mature RBCs were metabolically competent, as determined by enzymatic activities and elevated levels of mitochondria-derived metabolites. Metabolically-active mitochondria in RBCs may increase oxidative stress, which could facilitate and/or exacerbate SCD complications. Coculture of mitochondria-positive RBCs with neutrophils induced production of type 1 interferons, which are known to increase RBC alloimmunization rates. These data demonstrate that mitochondria retained in mature RBCs are functional and can elicit immune responses, suggesting that inappropriate retention of mitochondria in RBCs may play an underappreciated role in SCD complications and be an RBC alloimmunization risk factor.

The development of a safe, effective and affordable prophylactic vaccine against hepatitis C virus (HCV) remains a medical priority. Hepatitis B-C subviral envelope particles, which could be produced by industrial procedures adapted from those established for the hepatitis B virus vaccine, appear promising for use for this purpose. The prototype HBV-HCV bivalent vaccine-bearing genotype 1a HCV envelopes can induce neutralizing antibodies against this genotype, but is less effective against other genotypes. We show here, in a small animal model, that the use of a set of vaccine particles harbouring envelopes from different HCV genotypes in various association strategies can induce broad neutralizing protection or an optimized protection against a particular genotype prevalent in a given region, such as genotype 4 in Egypt. This vaccine could help to control the hepatitis C epidemic worldwide.

International audience; Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects throughout the viral lifecycle, with hepatic steatosis frequently observed in patients with chronic HCV infection. Hepatic steatosis is most common in patients infected with genotype 3 viruses, possibly due to direct effects of genotype 3 viral proteins. Hepatic steatosis in patients infected with other genotypes is thought to be mostly due to changes in host metabolism, involving insulin resistance in particular. Specific effects of the HCV genotype 3 core protein have been observed in cellular models in vitro: mechanisms linked to a decrease in microsomal triglyceride transfer protein activity, decreases in the levels of peroxisome proliferator-activating receptors, increases in the levels of sterol regulatory element-binding proteins, and phosphatase and tensin homologue downregulation. Functional differences between the core proteins of genotype 3 viruses and viruses of other genotypes may reflect differences in amino-acid sequences. However, bioclinical studies have failed to identify specific "steatogenic" sequences in HCV isolates from patients with hepatic steatosis. It is therefore difficult to distinguish between viral and metabolic steatosis unambiguously and host and viral factors are probably involved in both HCV genotype 3 and non-3 steatosis.

International audience; LDs (lipid droplets) are probably the least well-characterized cellular organelles. Having long been considered simple lipid storage depots, they are now considered to be dynamic organelles involved in many biological processes. However, most of the mechanisms driving LDs biogenesis, growth and intracellular movement remain largely unknown. As for other cellular mechanisms deciphered through the study of viral models, HCV (hepatitis C virus) is an original and relevant model for investigations of the birth and life of these organelles. Recent studies in this model have raised the hypothesis that the HCV core protein induces the redistribution of LDs through the regression and regeneration of these organelles in specific intracellular domains.

Lipid droplets are intracellular organelles involved not only in lipid storage, but also in cell signalling and the regulation of intracellular vesicular trafficking. Recent basic studies have suggested that interactions between hepatitis C virus (HCV) core protein and lipid droplets are required for the HCV infection cycle. In infected cells, the HCV core protein is associated with the surface of lipid droplets and the endoplasmic reticulum membranes closely surrounding these droplets, and its self-assembly drives virion budding. This interaction also seems to be directly linked to a virus-induced steatosis, which involves the deposition of triglycerides in the liver and contributes to the progression of fibrosis in patients with chronic hepatitis C. Many clinical studies have reported that virus-induced steatosis is significantly more severe with HCV genotype 3 than with other genotypes, and this phenomenon has been modelled in recent basic studies based on the production of HCV core proteins of various genotypes in vitro. The association of HCV core protein with lipid droplets seems to play a central role in HCV pathogenesis and morphogenesis, suggesting that virus-induced steatosis may be essential for the viral life cycle.

It is generally agreed that hepatitis B virus (HBV) replication is reduced by hepatitis delta virus infection (HDV) and augmented by human immunodeficiency virus (HIV) infection. However, the precise nature of the interactions between HBV, HDV and HIV is controversial. The aim of this study was to evaluate the impact of HIV infection on HBV and HDV replication, and on histological scores during delta virus superinfection in HDV-positive, chronic carriers of hepatitis B surface antigen (HBsAg). We studied 38 men and six women, 15 of whom were HIV-positive and all of whom had at least one marker of HDV infection. Serum hepatitis B e antigen (HBeAg), HBV DNA, HDV RNA, anti-delta antigen antibodies (anti-HD) IgM, anti-HD IgG and hepatitis delta antigen (HDAg) were tested for in the serum and liver, respectively; anti-hepatitis C virus (HCV) antibodies were detected using a second-generation recombinant immunoblot assay. Histological specimens were scored blindly according to Knodell's classification for periportal and intralobular necrosis, portal inflammation and fibrosis. HBV DNA was detected more frequently in the HIV-positive patients than in those who were HIV-negative (25 vs 0%; P = 0.01), while markers of HDV replication (serum anti-HD IgM, serum HDV RNA and liver HDAg) were as frequent in the HIV-positive patients (69%, 40% and 50%, respectively) as in those who were HIV-negative (75%, 52% and 30%, respectively; P > 0.05). By contrast, 31% of the HIV-positive patients were serum HDAg-positive compared to only 6% of the HIV-negative patients (P = 0.001). HDV antigenaemia and anti-HD antibodies usually fluctuated in the HIV-positive patients during follow-up. The mean Knodell score was similar in the HIV-positive (11.5 +/- 3.2) and HIV-negative (10.7 +/- 2) subgroups, as was the mean semi-quantitative index of hepatic necrosis, inflammation and fibrosis. Our results provide evidence that in HDV-positive patients: (1) HIV infection counters the inhibitory effect of HDV superinfection on HBV replication; (2) serum anti-HD IgM. HDV RNA and liver HDAg are not more frequent in HIV-positive than in HIV-negative patients, suggesting that HIV infection has no effect on HDV replication (although the significance of the increased frequency of HD antigenaemia remains unclear); (3) the histological severity of liver disease is not influenced by HIV status.

Synthesis of hitherto unknown carbocyclic α-L-isomeric bicyclo[3.1.0]hexyl nucleosides ( 8–11 ) is described. The key intermediate 7 was synthesized in seven steps from the known chiral compound 1 through a stereoselective cyclopropanation under Furukawa conditions. Compounds 8–11 were evaluated as anti-HBV agents in HepG2T14 cells.

The synthesis of several optically pure carbocyclic α-L-isomeric homonucleosides [3a-e, 6a,b, 7a,b, 10a-d] is reported. The (1R, 5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one 1 was used as a chiral starting material.

The prevalence of persistent hepatitis delta (HD) antigenaemia and associated factors in patients with chronic infection with the hepatitis delta virus (HDV) were investigated. Among 157 consecutive patients known to be carriers of hepatitis B surface antigen (HBsAg), 36 (23%) had one serum marker of HDV infection (anti-HD and/or HDAg). Nine of the patients with an HDV marker were HDAg positive, including three who were anti-HD negative. A follow-up over a mean period of 13 months showed that five of five patients had a persistent HD antigenaemia. This serological profile was associated with the presence of antibody to the human immunodeficiency virus (anti-HIV) (P < 0.01), serum HIV antigen (HlVAg) (P < 0.21, and the female sex (P < 0.05). Persistent HD antigenaemia could be the consequence of the suppression of T cell cytotoxic activity against hepatocytes expressing HDAg, a lower humoral response, and/or hormonal factors. © 1992 Wiley-Liss, Inc.