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Norbert Heinrich - One of the best experts on this subject based on the ideXlab platform.
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Seroprevalence of Alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggests endemic circulation of chikungunya.
PLoS Neglected Tropical Diseases, 2014Co-Authors: Nina Weller, Petra Clowes, Gerhard Dobler, Elmar Saathoff, Inge Kroidl, Nyanda E. Ntinginya, Leonard Maboko, Thomas Löscher, Michael Hoelscher, Norbert HeinrichAbstract:Background: To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. Methods: A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. Results: 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi. Conclusion: Alphavirus infections may contribute significantly to the febrile disease burden in the study area, and are associated with several arthropod-borne infections. Their spread seems only limited by factors affecting mosquitoes, and seems less restricted than that of Rift Valley fever.
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Seroprevalence of Alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggests endemic circulation of chikungunya.
PLoS neglected tropical diseases, 2014Co-Authors: Nina Weller, Petra Clowes, Gerhard Dobler, Elmar Saathoff, Inge Kroidl, Nyanda E. Ntinginya, Leonard Maboko, Thomas Löscher, Michael Hoelscher, Norbert HeinrichAbstract:To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi. Alphavirus infections may contribute significantly to the febrile disease burden in the study area, and are associated with several arthropod-borne infections. Their spread seems only limited by factors affecting mosquitoes, and seems less restricted than that of Rift Valley fever.
Kenneth Lundstrom - One of the best experts on this subject based on the ideXlab platform.
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Impact of a Plasmid DNA-Based Alphavirus Vaccine on Immunization Efficiency.
Methods in Molecular Biology, 2020Co-Authors: Kenneth LundstromAbstract:Alphavirus vectors have been engineered for high-level gene expression relying originally on replication-deficient recombinant particles, more recently designed for plasmid DNA-based administration. As Alphavirus-based DNA vectors encode the Alphavirus RNA replicon genes, enhanced transgene expression in comparison to conventional DNA plasmids is achieved. Immunization studies with Alphavirus-based DNA plasmids have elicited specific antibody production, have generated tumor regression and protection against challenges with infectious agents and tumor cells in various animal models. A limited number of clinical trials have been conducted with Alphavirus DNA vectors. Compared to conventional plasmid DNA-based immunization, Alphavirus DNA vectors required 1000-fold less DNA to elicit similar immune responses in rodents.
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Plasmid DNA-Based Alphavirus Vaccines
Vaccines, 2019Co-Authors: Kenneth LundstromAbstract:Alphaviruses have been engineered as vectors for high-level transgene expression. Originally, Alphavirus-based vectors were applied as recombinant replication-deficient particles, subjected to expression studies in mammalian and non-mammalian cell lines, primary cell cultures, and in vivo. However, vector engineering has expanded the application range to plasmid DNA-based delivery and expression. Immunization studies with DNA-based Alphavirus vectors have demonstrated tumor regression and protection against challenges with infectious agents and tumor cells in animal tumor models. The presence of the RNA replicon genes responsible for extensive RNA replication in the RNA/DNA layered Alphavirus vectors provides superior transgene expression in comparison to conventional plasmid DNA-based expression. Immunization with Alphavirus DNA vectors revealed that 1000-fold less DNA was required to elicit similar immune responses compared to conventional plasmid DNA. In addition to DNA-based delivery, immunization with recombinant Alphavirus particles and RNA replicons has demonstrated efficacy in providing protection against lethal challenges by infectious agents and tumor cells.
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Alphavirus vectors as tools in neuroscience and gene therapy
Virus Research, 2016Co-Authors: Kenneth LundstromAbstract:Alphavirus-based vectors have been engineered for in vitro and in vivo expression of heterelogous genes. The rapid and easy generation of replication-deficient recombinant particles and the broad range of host cell infection have made Alphaviruses attractive vehicles for applications in neuroscience and gene therapy. Efficient delivery to primary neurons and hippocampal slices has allowed localization studies of gene expression and electrophysiological recordings of ion channels. Alphavirus vectors have also been applied for in vivo delivery to rodent brain. Due to the strong local transient expression provided by Alphavirus vectors a number of immunization and gene therapy approaches have demonstrated both therapeutic and prophylactic efficacy in various animal models.
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Alphaviruses in gene therapy.
Viruses, 2015Co-Authors: Kenneth LundstromAbstract:Alphavirus vectors present an attractive approach for gene therapy applications due to the rapid and simple recombinant virus particle production and their broad range of mammalian host cell transduction. Mainly three types of Alphavirus vectors, namely naked RNA, recombinant particles and DNA/RNA layered vectors, have been subjected to preclinical studies with the goal of achieving prophylactic or therapeutic efficacy, particularly in oncology. In this context, immunization with Alphavirus vectors has provided protection against challenges with tumor cells. Moreover, Alphavirus intratumoral and systemic delivery has demonstrated substantial tumor regression and significant prolonged survival rates in various animal tumor models. Recent discoveries of the strong association of RNA interference and disease have accelerated gene therapy based approaches, where Alphavirus-based gene delivery can play an important role.
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Alphavirus-Based Vaccines
Viruses, 2014Co-Authors: Kenneth LundstromAbstract:Alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. The most commonly used delivery vectors are based on three single-stranded encapsulated Alphaviruses, namely Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus. Alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-proficient particles. Moreover, in vitro transcribed RNA, as well as layered DNA vectors have been applied for immunization. A large number of highly immunogenic viral structural proteins expressed from Alphavirus vectors have elicited strong neutralizing antibody responses in multispecies animal models. Furthermore, immunization studies have demonstrated robust protection against challenges with lethal doses of virus in rodents and primates. Similarly, vaccination with Alphavirus vectors expressing tumor antigens resulted in prophylactic protection against challenges with tumor-inducing cancerous cells. As certain Alphaviruses, such as Chikungunya virus, have been associated with epidemics in animals and humans, attention has also been paid to the development of vaccines against Alphaviruses themselves. Recent progress in Alphavirus vector development and vaccine technology has allowed conducting clinical trials in humans.
Scott C. Weaver - One of the best experts on this subject based on the ideXlab platform.
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a chimeric vesiculo Alphavirus is an effective Alphavirus vaccine
Journal of Virology, 2013Co-Authors: Anasuya Chattopadhyay, Scott C. Weaver, Eryu Wang, Robert L. Seymour, John K. RoseAbstract:While a large number of mosquito-transmitted Alphaviruses are known to cause serious human diseases, there are no licensed vaccines that protect against Alphavirus infections. The Alphavirus chikungunya virus (CHIKV) has caused multiple recent outbreaks of chikungunya fever. This virus has the potential to cause a worldwide epidemic and has generated strong interest in development of a prophylactic CHIKV vaccine. We report here on the development of a potent experimental vaccine for CHIKV based on a chimeric vesicular stomatitis virus (VSV) expressing the entire CHIKV envelope polyprotein (E3-E2-6K-E1) in place of the VSV glycoprotein (G). These VSVΔG-CHIKV chimeras incorporated functional CHIKV glycoproteins into the viral envelope in place of VSV G. The chimeric viruses were attenuated for growth in tissue culture but could be propagated to high titers without VSV G complementation. They also generated robust neutralizing antibody and cellular immune responses to CHIKV in mice after a single dose and protected mice against CHIKV infection. VSVΔG-Alphavirus chimeras could have general applicability as Alphavirus vaccines.
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A Chimeric Vesiculo/Alphavirus Is an Effective Alphavirus Vaccine
Journal of Virology, 2012Co-Authors: Anasuya Chattopadhyay, Scott C. Weaver, Eryu Wang, Robert L. Seymour, John K. RoseAbstract:While a large number of mosquito-transmitted Alphaviruses are known to cause serious human diseases, there are no licensed vaccines that protect against Alphavirus infections. The Alphavirus chikungunya virus (CHIKV) has caused multiple recent outbreaks of chikungunya fever. This virus has the potential to cause a worldwide epidemic and has generated strong interest in development of a prophylactic CHIKV vaccine. We report here on the development of a potent experimental vaccine for CHIKV based on a chimeric vesicular stomatitis virus (VSV) expressing the entire CHIKV envelope polyprotein (E3-E2-6K-E1) in place of the VSV glycoprotein (G). These VSVΔG-CHIKV chimeras incorporated functional CHIKV glycoproteins into the viral envelope in place of VSV G. The chimeric viruses were attenuated for growth in tissue culture but could be propagated to high titers without VSV G complementation. They also generated robust neutralizing antibody and cellular immune responses to CHIKV in mice after a single dose and protected mice against CHIKV infection. VSVΔG-Alphavirus chimeras could have general applicability as Alphavirus vaccines.
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Genome-Scale Phylogeny of the Alphavirus Genus Suggests a Marine Origin
Journal of Virology, 2011Co-Authors: Naomi L. Forrester, Scott C. Weaver, Gustavo Palacios, Robert B. Tesh, Nazir Savji, Hilda Guzman, Michael B. Sherman, W. I. LipkinAbstract:The genus Alphavirus comprises a diverse group of viruses, including some that cause severe disease. Using full-length sequences of all known Alphaviruses, we produced a robust and comprehensive phylogeny of the Alphavirus genus, presenting a more complete evolutionary history of these viruses compared to previous studies based on partial sequences. Our phylogeny suggests the origin of the Alphaviruses occurred in the southern oceans and spread equally through the Old and New World. Since lice appear to be involved in aquatic Alphavirus transmission, it is possible that we are missing a louse-borne branch of the Alphaviruses. Complete genome sequencing of all members of the genus also revealed conserved residues forming the structural basis of the E1 and E2 protein dimers.
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4 4 a cryo em structure of an enveloped Alphavirus venezuelan equine encephalitis virus
The EMBO Journal, 2011Co-Authors: Rui Zhang, Scott C. Weaver, Corey F Hryc, Yao Cong, Joanita Jakana, Rodion Gorchakov, Matthew L Baker, Wah ChiuAbstract:Venezuelan equine encephalitis virus (VEEV), a member of the membrane-containing Alphavirus genus, is a human and equine pathogen, and has been developed as a biological weapon. Using electron cryo-microscopy (cryo-EM), we determined the structure of an attenuated vaccine strain, TC-83, of VEEV to 4.4 A resolution. Our density map clearly resolves regions (including E1, E2 transmembrane helices and cytoplasmic tails) that were missing in the crystal structures of domains of Alphavirus subunits. These new features are implicated in the fusion, assembly and budding processes of Alphaviruses. Furthermore, our map reveals the unexpected E3 protein, which is cleaved and generally thought to be absent in the mature VEEV. Our structural results suggest a mechanism for the initial stage of nucleocapsid core formation, and shed light on the virulence attenuation, host recognition and neutralizing activities of VEEV and other Alphavirus pathogens.
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Alphavirus production is inhibited in neurofibromin 1 deficient cells through activated ras signalling
Virology, 2008Co-Authors: Olga A Kolokoltsova, Aaron M Domina, Andrey A Kolokoltsov, Robert A Davey, Scott C. Weaver, Stanley J WatowichAbstract:Abstract Virus–host interactions essential for Alphavirus pathogenesis are poorly understood. To address this shortcoming, we coupled retrovirus insertional mutagenesis and a cell survival selection strategy to generate clonal cell lines broadly resistant to Sindbis virus (SINV) and other Alphaviruses. Resistant cells had significantly impaired SINV production relative to wild-type (WT) cells, although virus binding and fusion events were similar in both sets of cells. Analysis of the retroviral integration sites identified the neurofibromin 1 (NF1) gene as disrupted in Alphavirus-resistant cell lines. Subsequent analysis indicated that expression of NF1 was significantly reduced in Alphavirus-resistant cells. Importantly, independent down-regulation of NF1 expression in WT HEK 293 cells decreased virus production and increased cell viability during SINV infection, relative to infected WT cells. Additionally, we observed hyperactive RAS signalling in the resistant HEK 293 cells, which was anticipated because NF1 is a negative regulator of RAS. Expression of constitutively active RAS (HRAS-G12V) in a WT HEK 293 cell line resulted in a marked delay in virus production, compared with infected cells transfected with parental plasmid or dominant-negative RAS (HRAS-S17N). This work highlights novel host cell determinants required for Alphavirus pathogenesis and suggests that RAS signalling may play an important role in neuronal susceptibility to SINV infection.
Nina Weller - One of the best experts on this subject based on the ideXlab platform.
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Seroprevalence of Alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggests endemic circulation of chikungunya.
PLoS Neglected Tropical Diseases, 2014Co-Authors: Nina Weller, Petra Clowes, Gerhard Dobler, Elmar Saathoff, Inge Kroidl, Nyanda E. Ntinginya, Leonard Maboko, Thomas Löscher, Michael Hoelscher, Norbert HeinrichAbstract:Background: To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. Methods: A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. Results: 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi. Conclusion: Alphavirus infections may contribute significantly to the febrile disease burden in the study area, and are associated with several arthropod-borne infections. Their spread seems only limited by factors affecting mosquitoes, and seems less restricted than that of Rift Valley fever.
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Seroprevalence of Alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggests endemic circulation of chikungunya.
PLoS neglected tropical diseases, 2014Co-Authors: Nina Weller, Petra Clowes, Gerhard Dobler, Elmar Saathoff, Inge Kroidl, Nyanda E. Ntinginya, Leonard Maboko, Thomas Löscher, Michael Hoelscher, Norbert HeinrichAbstract:To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi. Alphavirus infections may contribute significantly to the febrile disease burden in the study area, and are associated with several arthropod-borne infections. Their spread seems only limited by factors affecting mosquitoes, and seems less restricted than that of Rift Valley fever.
Nyanda E. Ntinginya - One of the best experts on this subject based on the ideXlab platform.
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Seroprevalence of Alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggests endemic circulation of chikungunya.
PLoS Neglected Tropical Diseases, 2014Co-Authors: Nina Weller, Petra Clowes, Gerhard Dobler, Elmar Saathoff, Inge Kroidl, Nyanda E. Ntinginya, Leonard Maboko, Thomas Löscher, Michael Hoelscher, Norbert HeinrichAbstract:Background: To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. Methods: A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. Results: 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi. Conclusion: Alphavirus infections may contribute significantly to the febrile disease burden in the study area, and are associated with several arthropod-borne infections. Their spread seems only limited by factors affecting mosquitoes, and seems less restricted than that of Rift Valley fever.
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Seroprevalence of Alphavirus antibodies in a cross-sectional study in southwestern Tanzania suggests endemic circulation of chikungunya.
PLoS neglected tropical diseases, 2014Co-Authors: Nina Weller, Petra Clowes, Gerhard Dobler, Elmar Saathoff, Inge Kroidl, Nyanda E. Ntinginya, Leonard Maboko, Thomas Löscher, Michael Hoelscher, Norbert HeinrichAbstract:To date, Alphavirus infections and their most prominent member, chikungunya fever, a viral disease which first became apparent in Tanzania in 1953, have been very little investigated in regions without epidemic occurrence. Few data exist on burden of disease and socio-economic and environmental covariates disposing to infection. A cross-sectional seroprevalence study was undertaken in 1,215 persons from Mbeya region, South-Western Tanzania, to determine the seroprevalence of anti-Alphavirus IgG antibodies, and to investigate associated risk factors. 18% of 1,215 samples were positive for Alphavirus IgG. Seropositivity was associated with participant age, low to intermediate elevation, flat terrain and with IgG positivity for Rift Valley fever, Flaviviridae, and rickettsiae of the spotted fever group. When comparing the geographical distribution of Alphavirus seropositivity to that of Rift Valley fever, it was obvious that Alphaviruses had spread more widely throughout the study area, while Rift Valley fever was concentrated along the shore of Lake Malawi. Alphavirus infections may contribute significantly to the febrile disease burden in the study area, and are associated with several arthropod-borne infections. Their spread seems only limited by factors affecting mosquitoes, and seems less restricted than that of Rift Valley fever.