{"doi":"10.1128/jvi.01766-16","title":"Ablation of Programmed −1 Ribosomal Frameshifting in Venezuelan Equine Encephalitis Virus Results in Attenuated Neuropathogenicity","abstract":"<jats:title>ABSTRACT</jats:title>\n                  <jats:p>\n                    The alphaviruses Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV) are arthropod-borne positive-strand RNA viruses that are capable of causing acute and fatal encephalitis in many mammals, including humans. VEEV was weaponized during the Cold War and is recognized as a select agent. Currently, there are no FDA-approved vaccines or therapeutics for these viruses. The spread of VEEV and other members of this family due to climate change-mediated vector range expansion underscores the need for research aimed at developing medical countermeasures. These viruses utilize programmed −1 ribosomal frameshifting (−1 PRF) to synthesize the viral\n                    <jats:italic>trans</jats:italic>\n                    -frame (TF) protein, which has previously been shown to be important for neuropathogenesis in the related Sindbis virus. Here, the alphavirus −1 PRF signals were characterized, revealing novel −1 PRF stimulatory structures. −1 PRF attenuation mildly affected the kinetics of VEEV accumulation in cultured cells but strongly inhibited its pathogenesis in an aerosol infection mouse model. Importantly, the decreased viral titers in the brains of mice infected with the mutant virus suggest that the alphavirus TF protein is important for passage through the blood-brain barrier and/or for neuroinvasiveness. These findings suggest a novel approach to the development of safe and effective live attenuated vaccines directed against VEEV and perhaps other closely related −1 PRF-utilizing viruses.\n                  </jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE</jats:bold>\n                    Venezuelan equine encephalitis virus (VEEV) is a select agent that has been weaponized. This arthropod-borne positive-strand RNA virus causes acute and fatal encephalitis in many mammals, including humans. There is no vaccine or other approved therapeutic. VEEV and related alphaviruses utilize programmed −1 ribosomal frameshifting (−1 PRF) to synthesize the viral\n                    <jats:italic>trans</jats:italic>\n                    -frame (TF) protein, which is important for neuropathogenesis. −1 PRF attenuation strongly inhibited VEEV pathogenesis in mice, and viral replication analyses suggest that the TF protein is critical for neurological disease. These findings suggest a new approach to the development of safe and effective live attenuated vaccines directed against VEEV and other related viruses.\n                  </jats:p>","journal":"Journal of Virology","year":2017,"id":17618,"datarank":1.5817675675271659,"base_score":4.04305126783455,"endowment":4.04305126783455,"self_citation_contribution":0.6064576901751826,"citation_network_contribution":0.9753098773519834,"self_endowment_contribution":0.6064576901751826,"citer_contribution":0.9753098773519834,"corpus_percentile":null,"corpus_rank":null,"citation_count":56,"citer_count":41,"citers_with_citation_signal":34,"citers_with_endowment":34,"datacite_reuse_total":6,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":125485,"name":"Cynthia de la Fuente","orcid":null,"position":1,"is_corresponding":false},{"id":125486,"name":"Ashwini Brahms","orcid":null,"position":2,"is_corresponding":false},{"id":125487,"name":"Caitlin Woodson","orcid":"0000-0002-8012-5377","position":3,"is_corresponding":false},{"id":125488,"name":"Todd M. Bell","orcid":null,"position":4,"is_corresponding":false},{"id":125489,"name":"Bin Chen","orcid":null,"position":5,"is_corresponding":false},{"id":59641,"name":"Yousuf A. Khan","orcid":"0000-0003-0201-2796","position":6,"is_corresponding":false},{"id":49669,"name":"Jonathan L. Jacobs","orcid":"0000-0001-5608-4256","position":7,"is_corresponding":false},{"id":124326,"name":"Kylene Kehn-Hall","orcid":"0000-0001-8036-7213","position":8,"is_corresponding":false},{"id":17814,"name":"Jonathan D. Dinman","orcid":"0000-0002-2402-9698","position":9,"is_corresponding":false},{"id":125484,"name":"Joseph A. Kendra","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.04305126783455,"endowment":4.04305126783455,"datacite_reuse_total":6,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27852852","pmcid":"PMC5244343","openalex_id":"https://openalex.org/W2553775999","authors":[],"funders":[{"funder_name":"HHS | National Institutes of Health","grant_id":"T32AI051967","title":null},{"funder_name":"DOD | Defense Threat Reduction Agency","grant_id":"HDTRA1-13-1-0005","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"T32 AI125186","title":null}],"total_grants":3,"fwci":4.6268,"citation_percentile":0.95151543,"influential_citations":5,"citation_trend":[{"year":2017,"count":2},{"year":2018,"count":6},{"year":2019,"count":7},{"year":2020,"count":6},{"year":2021,"count":9},{"year":2022,"count":8},{"year":2023,"count":5},{"year":2024,"count":8},{"year":2025,"count":1},{"year":2026,"count":3}],"oa_status":"bronze","license":"https://journals.asm.org/non-commercial-tdm-license","oa_locations":[{"url":"https://jvi.asm.org/content/jvi/91/3/e01766-16.full.pdf","host_type":"journal"},{"url":"https://jvi.asm.org/content/jvi/91/3/e01766-16.full.pdf","host_type":"BRONZE"},{"url":"https://jvi.asm.org/content/jvi/91/3/e01766-16.full.pdf","host_type":"publisher"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.01766-16","host_type":"publisher"},{"url":"https://doi.org/10.1128/jvi.01766-16","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/27852852","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5244343","host_type":"repository"}],"fields_of_study":["Mosquito-borne diseases and control","Viral Infections and Outbreaks Research","vaccines and immunoinformatics approaches","Biology","Medicine","Animals","Cell Line","Encephalitis Virus, Venezuelan Equine","Encephalomyelitis, Venezuelan Equine","Female","Frameshifting, Ribosomal","Genome, Viral","Horses","Humans","Nucleic Acid Conformation","Open Reading Frames","RNA, Messenger","RNA, Viral","Virus Replication"],"mesh_terms":["Animals","Cell Line","Encephalitis Virus, Venezuelan Equine","Encephalomyelitis, Venezuelan Equine","Female","Horses","Humans","Nucleic Acid Conformation","RNA, Messenger","RNA, Viral","Virus Replication","Open Reading Frames","Genome, Viral","Frameshifting, Ribosomal"],"keywords":["Translational frameshift","Biology","Virology","Venezuelan equine encephalitis virus","Virus","Encephalitis","Ribosome","Genetics","RNA","Gene","Vaccine","Alphavirus","Neuropathology","Ribosomal Frameshifting"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Climate action"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.26636175.v1","title":"Additional file 2 of Cell fusing agent virus isolated from Aag2 cells does not vertically transmit in Aedes aegypti via artificial infection","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26636175","title":"Additional file 2 of Cell fusing agent virus isolated from Aag2 cells does not vertically transmit in Aedes aegypti via artificial infection","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26636178.v1","title":"Additional file 3 of Cell fusing agent virus isolated from Aag2 cells does not vertically transmit in Aedes aegypti via artificial infection","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26636178","title":"Additional file 3 of Cell fusing agent virus isolated from Aag2 cells does not vertically transmit in Aedes aegypti via artificial infection","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26636172.v1","title":"Additional file 1 of Cell fusing agent virus isolated from Aag2 cells does not vertically transmit in Aedes aegypti via artificial infection","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26636172","title":"Additional file 1 of Cell fusing agent virus isolated from Aag2 cells does not vertically transmit in Aedes aegypti via artificial infection","publisher":"figshare","resource_type":"Dataset"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-02T19:34:18.809016Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}