{"doi":"10.1039/d3mo00025g","title":"Network modeling suggests HIV infection phenocopies PI3K-AKT pathway mutations to enhance HPV-associated cervical cancer","abstract":"Abstract Women coinfected with human immunodeficiency virus type 1 (HIV-1) and human papillomavirus (HPV) are six times as likely to develop invasive cervical carcinoma compared to those without HIV. Unlike other HIV-associated cancers, the risk of cervical cancer development does not change when HPV/HIV coinfected women begin antiretroviral therapy, suggesting HIV-associated immune suppression is not a key driver of cervical cancer development in coinfected women. Here, we investigated whether the persistent secretion of inflammatory factors in HIV-positive patients on antiretroviral therapy could enhance cancer signaling in HPV-infected cervical cells via endocrine mechanisms. We integrated previously reported HIV-induced secreted inflammatory factors (Hi-SIFs), HIV and HPV virus–human protein interactions, and cervical cancer patient genomic data using network propagation to understand the pathways underlying disease development in HPV/HIV coinfection. Our results pinpointed the PI3K-AKT signaling pathway to be enriched at the interface between Hi-SIFs and HPV–host molecular networks, in alignment with PI3K pathway mutations being prominent drivers of HPV-associated, but HIV independent, cervical cancer development. Furthermore, we experimentally stimulated cervical cells with 14 Hi-SIFs to assess their ability to activate PI3K-AKT signaling. Strikingly, we found 8 factors (CD14, CXCL11, CXCL9, CXCL13, CXCL17, AHSG, CCL18, and MMP-1) to significantly upregulate AKT phosphorylation (pAKT-S473) relative to a phosphate buffered saline control. Our findings suggest that Hi-SIFs cooperate with HPV infection in cervical cells to over-activate PI3K-AKT signaling, effectively phenocopying PI3K-AKT pathway mutations, resulting in enhanced cervical cancer development in coinfected women. Our insights could support the design of therapeutic interventions targeting the PI3K-AKT pathway or neutralizing Hi-SIFs in HPV/HIV coinfected cervical cancer patients.","journal":"Molecular Omics","year":2023,"id":359396,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.96,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1480,"name":"Jacqueline M. Fabius","orcid":null,"position":1,"is_corresponding":false},{"id":1493,"name":"Lorena Zuliani‐Alvarez","orcid":"0000-0002-4682-4043","position":2,"is_corresponding":false},{"id":1359,"name":"Manon Eckhardt","orcid":"0000-0001-8143-6129","position":3,"is_corresponding":false},{"id":415645,"name":"George B. Kyei","orcid":"0000-0002-8678-4656","position":4,"is_corresponding":false},{"id":388199,"name":"Peter K. Quashie","orcid":"0000-0003-4114-5460","position":5,"is_corresponding":false},{"id":1363,"name":"Nevan J. Krogan","orcid":"0000-0003-4902-337X","position":6,"is_corresponding":false},{"id":1455,"name":"Mehdi Bouhaddou","orcid":"0000-0002-9526-1427","position":7,"is_corresponding":false},{"id":746404,"name":"Yaw Bediako","orcid":"0000-0001-9786-7564","position":8,"is_corresponding":false},{"id":2390,"name":"Charles Ochieng’ Olwal","orcid":"0000-0003-1747-2963","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-19T01:13:52.889556Z","pmid":"37204043","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":[]}