{"doi":"10.3390/v17091176","title":"APOBEC3B Promotes SARS-CoV-2 Through Activation of PKR/eIF2⍺ and AMPD2 Dysregulation","abstract":"APOBEC3B (A3B) has been implicated in host-virus interactions, but its role in SARS-CoV-2 infection is unclear. Here, we demonstrate that A3B is overexpressed in bronchoalveolar lavage fluid (BALF) cells from severe COVID-19 patients compared to those with mild disease. A3B knockdown in Caco-2 cells significantly reduces SARS-CoV-2 infectivity, likely through attenuation of the PKR-mediated integrated stress response, a pathway proposed to promote SARS-CoV-2. Single-cell RNA sequencing (scRNA-seq) data suggest that BALF cells from severe COVID-19 patients exhibit a repressed state for cellular translation, potentially mediated by eIF2α phosphorylation. However, in A549-ACE2 cells, SARS-CoV-2 does not activate PKR, but A3B knockdown still reduces SARS-CoV-2 infectivity, suggesting an alternative mechanism of action in different cellular contexts. To further investigate A3B's role in severe COVID-19, we employed Geneformer, a transformer-based machine learning model, which predicted that A3B knockout would perturb AMPD2 (adenosine monophosphate deaminase 2), a key enzyme in purine metabolism and immune regulation. We validated this prediction using bulk RNA-seq and clinical scRNA-seq data, confirming that AMPD2 expression is downregulated in severe COVID-19 but restored upon A3B knockdown. Together, these findings suggest that A3B plays a proviral role in SARS-CoV-2 infection by modulating translational control and immune regulatory networks, warranting further studies to elucidate the underlying mechanistic details.","journal":"Viruses","year":2025,"id":573565,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9609,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":653739,"name":"Lavanya Manjunath","orcid":"0000-0003-1898-3570","position":1,"is_corresponding":false},{"id":876051,"name":"Philip Sell","orcid":"0009-0009-8636-5628","position":2,"is_corresponding":false},{"id":1103261,"name":"Shanshan Wang","orcid":"0009-0006-6645-762X","position":3,"is_corresponding":false},{"id":1262693,"name":"Tamara Margaryan","orcid":null,"position":4,"is_corresponding":false},{"id":1262692,"name":"Connor Qiu","orcid":null,"position":5,"is_corresponding":false},{"id":318108,"name":"Hanjing Yang","orcid":"0000-0001-7187-3720","position":6,"is_corresponding":false},{"id":270397,"name":"Rémi Buisson","orcid":"0000-0002-7196-8209","position":7,"is_corresponding":false},{"id":318117,"name":"Xiaojiang S. Chen","orcid":"0000-0001-9574-0551","position":8,"is_corresponding":false},{"id":1103262,"name":"Benjamin Fixman","orcid":"0000-0002-7592-3761","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:57:32.445190Z","pmid":"41012606","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":[]}