Year 2015
Antiviral drugs can cure Coxsackievirus B infection
A study by the partner in Lille evaluated if an antiviral drug can cure a persistent enterovirus infection in a pancreatic cell line. They tested fluoxetine which is widely used for other clinical indications but which has previously been reported to have also an antiviral effect against group B coxsackieviruses. These viruses have been considered as the main candidates for diabetogenic viruses in man, and a persistent coxsackie B virus infection in the pancreatic islets and potential mechanism of beta-cell damage. A dramatic decrease in viral titers was obtained in cells which were chronically infected by coxsackie B virus, and the virus was completely eradicated by a three weeks’ treatment. These results suggest that antiviral drugs could be used in clinical trials to test their efficacy against type 1 diabetes.
Reference:
Alidjinou EK, Sané F, Bertin A, Caloone D, Hober D. Persistent infection of human pancreatic cells with Coxsackievirus B4 is cured by fluoxetine. Antiviral Res. 2015 Apr;116:51-4.
The pancreatic islets of newly diagnosed type 1 diabetes patients are infected by enterovirus
The Diabetes Virus Detection study (DiViD) in the PEVNET consortium collected fresh pancreatic tissue from six living adult patients 3-9 weeks after the diagnosis of type 1 diabetes. These samples were tested for the presence of entero-, rhino-, parecho- noro- and rotaviruses and results were confirmed in collaboration of different PEVNET laboratories. Enterovirus protein was detected in the islets of all six patients using immunohistochemistry and enterovirus-specific RNA sequences were detected in isolated islets in four patients. All patients were negative for other tested viruses. The results were consistent in different laboratories. Class I HLA molecule was also upregulated in the islets of all patients suggesting ongoing virus-induced interferon secretion in the islets. Enterovirus protein was found in only 1,7% of islet cells and enterovirus genome concentration was low fitting with a slowly replicating virus and possible persistent infection in the islets. This is the first study demonstrating enterovirus infection in the islet cells of living newly diagnosed type 1 diabetes patients. These results do not confirm the causality between enterovirus and type 1 diabetes, but emphasize the importance of development of antiviral medication and vaccines against possible diabetogenic enteroviruses.
Reference:
Krogvold L, Edwin B, Buanes T, Frisk G, Skog O, Anagandula M, Korsgren O, Undlien D, Eike MC, Richardson SJ, Leete P, Morgan NG, Oikarinen S, Oikarinen M, Laiho JE, Hyöty H, Ludvigsson J, Hanssen KF, Dahl-Jørgensen K. Detection of a low-grade enteroviral infection in the islets of langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes. 2015 May;64(5):1682-7.
Year 2014
A subgroup of enteroviruses is associated with type 1 diabetes in large scale epidemiological studies
During the year 2014 two independent studies were published in the same issue of the Diabetes journal evaluating if the risk association between enteroviruses and type 1 diabetes is associated with certain specific enterovirus types or if it is related to a wide range of different enteroviruses. This question is fundamentally important for possible development of preventive vaccines. One of these studies was carried out in the Finnish prospective DIPP study, which follows children from birth until some of them develop islet autoimmunity or clinical type 1 diabetes. The results suggested that one genetically narrow subgroup of enteroviruses, the group of coxsackie B viruses, is associated with the risk of type 1 diabetes. These viruses include altogether six serotypes and one of them, coxsackievirus B1, was associated with increased risk of islet autoimmunity and type 1 diabetes. Other coxsackie B serotypes modulated this risk association with an interaction pattern, suggesting immunological cross-protection against coxsackievirus B1.
The other study was designed to validate these findings in other populations. It was based on the VirDiab study cohort, which included newly diagnosed type 1 diabetes patients and carefully matched control subjects from different European countries. Antibodies against coxsackievirus B1 were again more frequently observed in type 1 diabetic patients than in controls, while antibodies against other coxsackie B viruses did not differ between the groups.
These results support previous observations suggesting that the group B coxsackieviruses are associated with the risk of type 1 diabetes. The clustering of the risk and protective viruses to this narrow phylogenetic lineage supports the biological plausibility of this phenomenon. This opens also possibilities to study the mechanisms of virus-induced diabetes and to develop vaccines against these viruses and test their efficacy against type 1 diabetes in preclinical and clinical trials.
References:
Laitinen OH, Honkanen H, Pakkanen O, Oikarinen S, Hankaniemi MM, Huhtala H, Ruokoranta T, Lecouturier V, André P, Harju R, Virtanen SM, Lehtonen J, Almond JW, Simell T, Simell O, Ilonen J, Veijola R, Knip M, Hyöty H. Coxsackievirus B1 is associated with induction of β-cell autoimmunity that portends type 1 diabetes. Diabetes. 2014 Feb;63(2):446-55.
Oikarinen S, Tauriainen S, Hober D, Lucas B, Vazeou A, Sioofy-Khojine A, Bozas E, Muir P, Honkanen H, Ilonen J, Knip M, Keskinen P, Saha MT, Huhtala H, Stanway G, Bartsocas C, Ludvigsson J, Taylor K, Hyöty H; VirDiab Study Group. Virus antibody survey in different European populations indicates risk association between coxsackievirus B1 and type 1 diabetes. Diabetes. 2014 Feb;63(2):655-62.
Virus-like particle vaccine is effective against coxsackie B virus
Virus-like particle (VLP) technology offers several advantages over traditional vaccine technologies and first VLP-vaccines are on the market. Therefore, the applicability of this technology in the production of vaccines against coxsackie B viruses was evaluated. The study established an efficient and scalable ion exchange chromatography-based purification method for baculovirus-insect cell-expressed coxsackie B-VLPs which is relevant for vaccine production on an industrial scale. The produced VLPs were characterized using a number of biophysical methods and exhibited excellent quality and high purity. Immunization of mice with VLPs elicited a strong immune response, demonstrating the excellent vaccine potential of these VLPs.
Reference:
Koho T, Koivunen MR, Oikarinen S, Kummola L, Mäkinen S, Mähönen AJ, Sioofy-Khojine A, Marjomäki V, Kazmertsuk A, Junttila I, Kulomaa MS, Hyöty H, Hytönen VP, Laitinen OH. Coxsackievirus B3 VLPs purified by ion exchange chromatography elicit strong immune responses in mice. Antiviral Res. 2014 Apr;104:93-101.
The first preclinical test of a vaccine targeting virus-induced type 1 diabetes
A recent collaborative study published by scientists in the PEVNET consortium, Vactech Oy and Sanofi Pasteur suggests that a vaccine targeting virus-induced type 1 diabetes may be feasible.
The authors performed a preclinical study of a monovalent vaccine targeting Coxsackievirus B1, a virus recently identified to be of diabetogenic nature. The study shows that the vaccine protects against infection without causing adverse side effects or triggering autoimmunity [1].
These results are promising for the clinical development of multivalent vaccines targeting viruses associated with type 1 diabetes, in an attempt to protect from the disease.
Reference:
Larsson PG, Lakshmikanth T, Laitinen OH, et al. (2014) A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models. Diabetologia (2015) 58:346–354