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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\u2013human 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\u2013host 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.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1039\/d3mo00025g","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T06:46:40Z","timestamp":1684478800000},"page":"538-551","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Network modeling suggests HIV infection phenocopies PI3K-AKT pathway mutations to enhance HPV-associated cervical cancer"],"prefix":"10.1093","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1747-2963","authenticated-orcid":false,"given":"Charles Ochieng\u2019","family":"Olwal","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana b , Accra, Ghana"},{"name":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana a , Accra, Ghana ybediako@ug.edu.gh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M","family":"Fabius","sequence":"additional","affiliation":[{"name":"The Cancer Cell Map Initiative, San Francisco and La Jolla e , CA, USA"},{"name":"Quantitative Biosciences Institute, University of California d , San Francisco, CA, USA"},{"name":"The J. David Gladstone Institute of Data Science and Biotechnology c , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Zuliani-Alvarez","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, University of California f , San Francisco, CA, USA Nevan.krogan@ucsf.edu"},{"name":"The Cancer Cell Map Initiative, San Francisco and La Jolla e , CA, USA"},{"name":"Quantitative Biosciences Institute, University of California d , San Francisco, CA, USA"},{"name":"The J. David Gladstone Institute of Data Science and Biotechnology c , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Eckhardt","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, University of California f , San Francisco, CA, USA Nevan.krogan@ucsf.edu"},{"name":"Quantitative Biosciences Institute, University of California d , San Francisco, CA, USA"},{"name":"The J. David Gladstone Institute of Data Science and Biotechnology c , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George Boateng","family":"Kyei","sequence":"additional","affiliation":[{"name":"University of Ghana Medical Centre, University of Ghana h , Accra, Ghana"},{"name":"Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana g , Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Kojo","family":"Quashie","sequence":"additional","affiliation":[{"name":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana a , Accra, Ghana ybediako@ug.edu.gh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevan J","family":"Krogan","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, University of California f , San Francisco, CA, USA Nevan.krogan@ucsf.edu"},{"name":"The Cancer Cell Map Initiative, San Francisco and La Jolla e , CA, USA"},{"name":"Quantitative Biosciences Institute, University of California d , San Francisco, CA, USA"},{"name":"The J. David Gladstone Institute of Data Science and Biotechnology c , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Bouhaddou","sequence":"additional","affiliation":[{"name":"Molecular Biology Institute, University of California k , Los Angeles, LA, USA"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California j , Los Angeles, LA, USA Bouhaddou@ucla.edu"},{"name":"Institute for Quantitative and Computational Biosciences (QCBio), University of California i , Los Angeles, LA, USA"},{"name":"Quantitative Biosciences Institute, University of California d , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaw","family":"Bediako","sequence":"additional","affiliation":[{"name":"Yemaachi Biotech l , Accra, Ghana"},{"name":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana a , Accra, Ghana ybediako@ug.edu.gh"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,19]]},"reference":[{"key":"2026010813045418300_cit1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"Sung","year":"2021","journal-title":"Ca-Cancer J. 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