{"doi":"10.1128/jvi.00931-14","title":"Kaposi's Sarcoma-Associated Herpesvirus ORF45 Mediates Transcriptional Activation of the HIV-1 Long Terminal Repeat via RSK2","abstract":"<jats:title>ABSTRACT</jats:title><jats:p>Robust activation of human immunodeficiency virus type 1 (HIV-1) gene expression occurs upon superinfection with Kaposi's sarcoma-associated herpesvirus (KSHV), a common AIDS-associated pathogen. Though the mechanisms underlying this phenotype remain unknown, several KSHV-encoded factors have been reported to stimulate HIV-1 long terminal repeat (LTR) activity. Here, we systematically evaluated the ability of KSHV tegument proteins to modulate the activation of an integrated HIV-1 LTR and revealed that the most potent individual activator is ORF45. ORF45 directs an increase in RNA polymerase II recruitment to the HIV-1 LTR, leading to enhanced transcriptional output. ORF45 is a robust activator of the p90 ribosomal S6 kinases (RSK), and we found that this activity is necessary but not sufficient to increase transcription from the LTR. Of the three widely expressed RSK isoforms, RSK2 appears to be selectively involved in LTR stimulation by both KSHV ORF45 and HIV-1 Tat. However, constitutively active RSK2 is unable to stimulate the LTR, suggesting that ORF45 may preferentially direct this kinase to a specific set of targets. Collectively, our findings reveal a novel transcriptional activation function for KSHV ORF45 and highlight the importance of RSK2 in shaping the transcriptional environment during infection.</jats:p><jats:p><jats:bold>IMPORTANCE</jats:bold>Kaposi's sarcoma-associated herpesvirus (KSHV) is a prominent AIDS-associated pathogen. Previous studies have shown that infection of cells containing human immunodeficiency virus type 1 (HIV-1) with KSHV leads to potent stimulation of HIV-1 gene expression by activating the HIV-1 promoter, termed the long terminal repeat (LTR). Here, we compared the abilities of various KSHV proteins to activate gene expression from the HIV-1 LTR and found that KSHV ORF45 is the most potent activator. ORF45 is known to induce cell signaling through ribosomal S6 kinase (RSK) and enhance protein translation. However, we revealed that the activation of a specific isoform of RSK by ORF45 also leads to increased mRNA synthesis from the LTR by the host RNA polymerase. Collectively, our findings provide new insight into the interviral interactions between KSHV and HIV that may ultimately impact disease.</jats:p>","journal":"Journal of Virology","year":2014,"id":14792,"datarank":1.0912750982535873,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.6419152572204886,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.6419152572204886,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":18,"citers_with_citation_signal":17,"citers_with_endowment":17,"datacite_reuse_total":1,"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":115363,"name":"Yang Zhao","orcid":null,"position":1,"is_corresponding":false},{"id":115364,"name":"Bret Peterson","orcid":null,"position":2,"is_corresponding":false},{"id":115365,"name":"Qiang Zhou","orcid":null,"position":3,"is_corresponding":false},{"id":115366,"name":"Britt Glaunsinger","orcid":null,"position":4,"is_corresponding":false},{"id":115362,"name":"John Karijolich","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":2.995732273553991,"endowment":2.995732273553991,"datacite_reuse_total":1,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24719417","pmcid":"PMC4054375","openalex_id":"https://openalex.org/W2145043974","authors":[],"funders":[{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI095057","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI041757","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01AI41757","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01AI041757-07","title":"Regulation of Transcriptional Elongation by HIV-1 TAT"}],"total_grants":4,"fwci":1.9391,"citation_percentile":0.87254343,"influential_citations":3,"citation_trend":[{"year":2014,"count":1},{"year":2015,"count":5},{"year":2016,"count":3},{"year":2017,"count":4},{"year":2018,"count":2},{"year":2021,"count":1},{"year":2022,"count":2},{"year":2023,"count":1}],"oa_status":"bronze","license":"ASM Journals Non-Commercial TDM","oa_locations":[{"url":"https://jvi.asm.org/content/jvi/88/12/7024.full.pdf","host_type":"journal"},{"url":"https://europepmc.org/articles/pmc4054375?pdf=render","host_type":"GREEN"},{"url":"https://jvi.asm.org/content/jvi/88/12/7024.full.pdf","host_type":"publisher"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.00931-14","host_type":"publisher"},{"url":"https://doi.org/10.1128/jvi.00931-14","host_type":"journal"},{"url":"https://escholarship.org/uc/item/6b98p5gc","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4054375","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24719417","host_type":""},{"url":"https://dx.doi.org/10.1128/jvi.00931-14","host_type":""},{"url":"https://doi.org/https://doi.org/10.1128/jvi.00931-14","host_type":""}],"fields_of_study":["Viral-associated cancers and disorders","Herpesvirus Infections and Treatments","HIV Research and Treatment","Biology","Medicine","0301 basic medicine","0303 health sciences","03 medical and health sciences","Animals","Cell Line","Coinfection","HIV Infections","HIV Long Terminal Repeat","HIV-1","Herpesviridae Infections","Herpesvirus 8, Human","Humans","Immediate-Early Proteins","Mice","Ribosomal Protein S6 Kinases, 90-kDa","Transcriptional Activation"],"mesh_terms":["Cell Line","Animals","Humans","Mice","Herpesvirus 8, Human","HIV-1","Herpesviridae Infections","HIV Infections","Ribosomal Protein S6 Kinases, 90-kDa","Immediate-Early Proteins","HIV Long Terminal Repeat","Transcriptional Activation","Coinfection"],"keywords":["Biology","Long terminal repeat","HIV Long Terminal Repeat","Kaposi's sarcoma-associated herpesvirus","Transactivation","Virology","Transcription (linguistics)","Activator (genetics)","Gene","Promoter","Ribosomal s6 kinase","Virus","Gene expression","Cell biology","Genetics","Signal transduction","Herpesviridae","Viral disease","HIV Infections","Virology (science-metrix)","2.2 Factors relating to the physical environment (hrcs-rac)","Herpesviridae Infections (mesh)","Human (mesh)","11 Medical and Health Sciences (for)","Medical and Health Sciences","Mice","veterinary and food sciences","31 Biological sciences (for-2020)","2.1 Biological and endogenous factors","2.2 Factors relating to the physical environment","Animals (mesh)","HIV Long Terminal Repeat (mesh)","Transcriptional Activation (mesh)","32 Biomedical and Clinical Sciences (for-2020)","Humans (mesh)","Coinfection (mesh)","Coinfection","Mice (mesh)","Herpesviridae Infections","Biological Sciences","06 Biological Sciences (for)","07 Agricultural and Veterinary Sciences (for)","Infection (hrcs-hc)","Infectious Diseases","Medical Microbiology","Herpesvirus 8, Human","HIV/AIDS","Infection","Human","Transcriptional Activation","570","90-kDa (mesh)","Immunology","610","HIV Infections (mesh)","30 Agricultural","Ribosomal Protein S6 Kinases, 90-kDa","90-kDa","Emerging Infectious Diseases (rcdc)","Cell Line","Immediate-Early Proteins","veterinary and food sciences (for-2020)","Animals","Humans","3207 Medical Microbiology (for-2020)","Herpesvirus 8","Immediate-Early Proteins (mesh)","3204 Immunology (for-2020)","Agricultural","HIV/AIDS (rcdc)","HIV-1 (mesh)","Biomedical and Clinical Sciences","Agricultural and Veterinary Sciences","Genetics (rcdc)","Ribosomal Protein S6 Kinases","2.1 Biological and endogenous factors (hrcs-rac)","Emerging Infectious Diseases","Infectious Diseases (rcdc)","Cell Line (mesh)","HIV-1","Sexually Transmitted Infections","Sexually Transmitted Infections (rcdc)"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[{"doi":"10.17920/g9pn7m","title":"A viral tool to reactivate latent HIV","publisher":"University of California Office of the President","resource_type":"Award"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-01T14:39:19.338082Z","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":[]}