A primary therapeutic goal in Alzheimer's disease (AD) is to reduce the quantity of amyloid β protein (Aβ) present in the brain. To develop an effective, safe system for vaccination against ...Alzheimer's disease, the plant virus
Cucumber mosaic virus (CMV) was engineered genetically to express Aβ-derived fragments that stimulate mainly humoral immune responses. Six chimeric constructs, bearing the Aβ1–15 or the Aβ4–15 sequence in positions 248, 392 or 529 of the CMV coat protein (CP) gene, were created. Viral products proved to be able to replicate in their natural host. However, only chimeric Aβ1–15-CMVs were detected by Aβ1–42 antiserum in Western blot analysis.
Experimental evidence of Immunoelectron microscopy revealed a complete decoration of Aβ1–15-CMV
248 and Aβ1–15-CMV
392 following incubation with either anti-Aβ1–15 or anti-Aβ1–42 polyclonal antibodies. These two chimeric CMVs appear to be endowed with features making them possible candidates for vaccination against Alzheimer's disease.
The combination of pegylated interferon (Peg‐IFN) and ribavirin is currently the gold standard therapy in patients with HCV chronic infection. The duration of therapy, as well as the therapeutic ...dosage, depend on the genotype. Identification of the genotype and rapid virological response (RVR) are widely accepted as the most important predictors of clinical outcome during antiviral therapy but to optimize cost‐benefits and to reduce possible side effects, further prognostic factors are needed. Squamous cell carcinoma antigens immunocomplex (SCCA‐IC) has been reported to be increased in the serum of patients with liver cancer. In this multicentric prospective study, we investigated the serum levels of SCCA‐IC in 103 patients with HCV chronic infection. Serum HCV‐RNA was detected before the beginning of treatment, after 4, 12, 24 or 48 weeks, and at week 24 during follow‐up. RVR, early virological response and sustained virological response (SVR) were assessed following the international guidelines. SCCA‐IC levels were higher in responders (238 AU, interquartile difference 130–556 AU) and decreased significantly to 125 AU (70–290 AU). The mean baseline value in nonresponders was 149 AU (86.5–306.5 AU), but after 4 weeks of treatment the serum levels decreased to 115 AU (80–280 AU): the profile of reduction was different between patients with or without a positive SVR. Logistic regression with SVR as dependent variable identified as significant independent variables: the reduction in SCCA‐IC after 1 month (OR = 4.82; 95% CI 1.39–16.67; P = 0.131) and a genotype other than 1 (OR = 0.094; 95% CI 0.21–0.42; P = 0.002); sex and age were also significant factors influencing SVR. SCCA‐IC seems to be a reliable independent prognostic marker of therapeutic effectiveness in anti‐HCV positive patients undergoing antiviral therapy.
The role of apoptosis in the persistence of hepatitis C virus (HCV) infection is controversial. Moreover, conflicting data on the modulation of this process by HCV proteins have been provided. We ...evaluated the susceptibility of peripheral lymphocytes from patients with chronic hepatitis C to apoptosis both spontaneous and after incubation with a chimeric
Cucumber mosaic virus
(CMV) carrying 180 copies of the synthetic R9 mimotope obtained from more than 200 hypervariable region-1 sequences of HCV. Resting T lymphocytes were found to be sensitized to apoptosis as a result of chronic HCV infection. The plant virus-derived vector R9-CMV displayed a strong pro-apoptotic effect associated with activation of both caspase-8 and −9, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. A parallel R9-CMV-mediated activation of endoplasmic reticulum-stress was suggested by the significant induction of BiP/GRP78, GADD153 and caspase-12. These data contribute to define the complex HCV/host interaction, and open new prospects for developing a plant-derived antigen-presenting system to strengthen host defences against persistent pathogens.
Cucumber mosaic virus (CMV) is a three component isodiametric plant virus which is common worldwide and has an extremely wide host range. A pseudorecombinant was made, derived from the RNA3 component ...of the CMV-S strain, carrying the coat protein (CP) gene, and the RNA1,2 components of the CMV-D strain. This system developed mild mosaic and vein clearing in Xanthi tobacco three weeks after inoculation. The CP gene was then engineered in three different positions, to encode a Hepatitis C virus (HCV) epitope. The selected peptide was the so-called R9 mimotope, a synthetic surrogate derived from a consensus profile of many hypervariable region 1 (HVR1) sequences of the putative HCV envelope protein E2. Serum samples from 60 patients with chronic hepatitis C displayed a significant immunoreactivity to crude plant extracts infected with the chimeric CMV. These results suggest that further investigation should be made into a possible vaccine function for the CMV-HCV mimotope system.
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Despite improvements in diagnostic and therapeutic interventions, prognosis and survival are still poor. To ...identify factors influencing survival, we retrospectively examined 150 consecutive patients with HCC from the time of first diagnosis of cirrhosis to death. In a multivariate analysis, we found that patients with larger HCC lesions had shorter survival, while other pathologic features had no predictive value. The most important and reliable prognostic factor was the occurrence of tumor thrombus of the portal vein (
P<0.01). Child's stage of underlying liver disease was relevant only in the univariate, but not in the multivariate analysis. The survival of patients with HCC is mainly affected by the biological ability of cancer cells to invade surrounding tissue and vessels. More studies are needed to elucidate the mechanisms that modulate tumor cell motility, in order to design more effective therapies.
A vaccine against Hepatitis C virus (HCV) is urgently needed due to the unsatisfactory clinical response to current therapies. We evaluated the immunological properties of a chimeric Cucumber mosaic ...virus (CMV), a plant virus engineered to express on its surface a synthetic peptide derived from many HVR1 sequences of the HCV envelope protein E2 (R9 mimotope). Evidence was obtained that the chimeric R9-CMV elicits a specific humoral response in rabbits. Furthermore, in patients with chronic HCV infection, purified preparations of R9-CMV down-modulated the lymphocyte surface density of CD3 and CD8, and induced a significant release of interferon (IFN)-gamma, interleukin (IL)-12 p70 and IL-15 by lymphomonocyte cultures. Finally, an R9 mimotope-specific CD8 T-cell response, as assessed by intracellular IFN-gamma production, was achieved in the majority of the patients studied. Our results open up new prospects for the development of effective vaccines against HCV infection. Moreover, the wide edible host range of CMV makes the production of an edible vaccine conceivable.
MxA and PKR expression in chronic hepatitis C Giannelli, Gianluigi; Guadagnino, Graziana; Dentico, Pietro ...
Journal of interferon & cytokine research,
11/2004, Letnik:
24, Številka:
11
Journal Article
Recenzirano
The effectiveness of therapy for chronic hepatitis C (CHC) patients has greatly improved in the last few years, and the gold standard is currently held to be pegylated interferon (IFN) in combination ...with ribavirin. Overall, however, the percentage of patients achieving a sustained virologic response (SVR) is only around 50%,and it is not possible to predict those patients who will benefit from therapy. The molecular mechanisms underlying lack of therapeutic response remain unknown. In this study, we investigated the tissue expression of MxA and RNA-dependent protein kinase (PKR), two antiviral proteins modulated by IFN, in biopsy samples from hepatitis C patients before the beginning of therapy. Our results show that expression of MxA, but not of PKR, is significantly lower in responders compared with nonresponders. No differences were observed regarding the hepatitis C virus (HCV) genotype and the viral load. These results suggest that expression of the MxA protein could play a role among the mechanisms underlying responsiveness to therapy.
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