{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:02:33Z","timestamp":1760058153198,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PNRR\/2022\/C9\/MCID\/I8-Development","award":["760252\/28.12.2023"],"award-info":[{"award-number":["760252\/28.12.2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Non-Hodgkin lymphoma (NHL) remains the most common malignancy and cause of death among human immunodeficiency virus (HIV-1)-positive individuals, its prevalence remaining even after the introduction of combined antiretroviral therapy (cART). The mechanisms underlying B-cell tumorigenesis are still poorly understood; however, recently, a key role for p17 variants (vp17s) in lymphoma development has been clearly elucidated. Here, we describe findings on lymphomagenic vp17s and discuss their potential role as diagnostic and prognostic markers that could be used to predict the HIV-positive patients at higher risk of developing lymphoma. Specifically, vp17s endowed with amino acid (aa) insertions in their C-terminal region, at positions 114\u2013115 (Glu-Lys), 117\u2013118 (Ala\u2013Ala) and 125\u2013126 (Gly\u2013Asp), were found to be significantly more prevalent in HIV-positive individuals with lymphoma as compared to those without. Alterations in the primary aa sequences destabilize the protein, exposing a previously hidden functional epitope which interacts with protease-activated receptor-1 (PAR-1) and stimulates the protein kinase B pathway, conferring oncogenic potential to vp17s and possibly contributing to lymphomagenesis. Therefore, ultradeep sequencing technologies, such as next-generation sequencing, could serve as a valuable screening tool for identifying and monitoring the HIV-positive patients at higher risk of developing lymphoma, paving the way for targeted preventive intervention strategies.<\/jats:p>","DOI":"10.3390\/v17040463","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:48:20Z","timestamp":1742824100000},"page":"463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["p17 Variant Expression and Evolution in HIV-Mediated Lymphomagenesis"],"prefix":"10.3390","volume":"17","author":[{"given":"Nicoleta","family":"Arnaut","sequence":"first","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, \u201cGeorge Emil Palade\u201d University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3767-4861","authenticated-orcid":false,"given":"Mark","family":"Slevin","sequence":"additional","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, \u201cGeorge Emil Palade\u201d University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"B\u0103nescu","sequence":"additional","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, \u201cGeorge Emil Palade\u201d University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania"},{"name":"Genetics Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihaela","family":"Straist\u0103","sequence":"additional","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, \u201cGeorge Emil Palade\u201d University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnaldo","family":"Caruso","sequence":"additional","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, \u201cGeorge Emil Palade\u201d University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania"},{"name":"Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-9033","authenticated-orcid":false,"given":"Francesca","family":"Caccuri","sequence":"additional","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, \u201cGeorge Emil Palade\u201d University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania"},{"name":"Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e295","DOI":"10.1016\/S2352-3018(23)00028-0","article-title":"Life Expectancy after 2015 of Adults with HIV on Long-Term Antiretroviral Therapy in Europe and North America: A Collaborative Analysis of Cohort Studies","volume":"10","author":"Trickey","year":"2023","journal-title":"Lancet HIV"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1080\/17571472.2014.11493422","article-title":"The Prevalence of Comorbidities among People Living with HIV in Brent: A Diverse London Borough","volume":"6","author":"Lorenc","year":"2014","journal-title":"Lond. J. Prim. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e495","DOI":"10.1016\/S2352-3018(17)30125-X","article-title":"Cancer Risk in HIV-Infected People in the USA from 1996 to 2012: A Population-Based, Registry-Linkage Study","volume":"4","author":"Shiels","year":"2017","journal-title":"Lancet HIV"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1097\/QAD.0000000000000222","article-title":"Causes of Death among HIV-Infected Patients in France in 2010 (National Survey): Trends since 2000","volume":"28","author":"Morlat","year":"2014","journal-title":"AIDS"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.semcancer.2015.06.002","article-title":"Microenvironment and HIV-Related Lymphomagenesis","volume":"34","author":"Pantanowitz","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1182\/blood-2015-11-681411","article-title":"A Lymphomagenic Role for HIV beyond Immune Suppression?","volume":"127","author":"Dolcetti","year":"2016","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e2122050119","DOI":"10.1073\/pnas.2122050119","article-title":"HIV-1 Mutants Expressing B Cell Clonogenic Matrix Protein P17 Variants Are Increasing Their Prevalence Worldwide","volume":"119","author":"Caccuri","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Giagulli, C., Marsico, S., Magiera, A.K., Bruno, R., Caccuri, F., Barone, I., Fiorentini, S., And\u00f2, S., and Caruso, A. (2011). Opposite Effects of HIV-1 P17 Variants on PTEN Activation and Cell Growth in B Cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017831"},{"key":"ref_9","first-page":"1","article-title":"Functions of the HIV-1 Matrix Protein P17","volume":"29","author":"Fiorentini","year":"2006","journal-title":"New Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Reuse, S., Calao, M., Kabeya, K., Guiguen, A., Gatot, J.-S., Quivy, V., Vanhulle, C., Lamine, A., Vaira, D., and Demonte, D. (2009). Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications for Treatment of Latent Infection. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006093"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1016\/j.bcp.2007.02.011","article-title":"HIV-1 Protease Inhibitors Do Not Interfere with Provirus Transcription and Host Cell Apoptosis Induced by Combined Treatment TNF-Alpha + TSA","volume":"73","author":"Vandergeeten","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Caccuri, F., Iaria, M.L., Campilongo, F., Varney, K., Rossi, A., Mitola, S., Schiarea, S., Bugatti, A., Mazzuca, P., and Giagulli, C. (2016). Cellular Aspartyl Proteases Promote the Unconventional Secretion of Biologically Active HIV-1 Matrix Protein P17. Sci. Rep., 6.","DOI":"10.1038\/srep38027"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bugatti, A., Caccuri, F., Filippini, F., Ravelli, C., and Caruso, A. (2021). Binding to PI(4,5)P2 Is Indispensable for Secretion of B-Cell Clonogenic HIV-1 Matrix Protein P17 Variants. J. Biol. Chem., 297.","DOI":"10.1016\/j.jbc.2021.100934"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1073\/pnas.0800370105","article-title":"HIV-1 Matrix Protein P17 Induces Human Plasmacytoid Dendritic Cells to Acquire a Migratory Immature Cell Phenotype","volume":"105","author":"Fiorentini","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"114858","DOI":"10.1016\/j.jviromet.2023.114858","article-title":"Detection of HIV-1 Matrix Protein P17 in Sera of Viremic and Aviremic Patients","volume":"324","author":"Zani","year":"2024","journal-title":"J. Virol. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e0120021","DOI":"10.1128\/JVI.01200-21","article-title":"The HIV-1 Matrix Protein P17 Does Cross the Blood-Brain Barrier","volume":"96","author":"Caccuri","year":"2022","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zeinolabediny, Y., Caccuri, F., Colombo, L., Morelli, F., Romeo, M., Rossi, A., Schiarea, S., Ciaramelli, C., Airoldi, C., and Weston, R. (2017). HIV-1 Matrix Protein P17 Misfolding Forms Toxic Amyloidogenic Assemblies That Induce Neurocognitive Disorders. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-10875-0"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14807","DOI":"10.1073\/pnas.0506857102","article-title":"Persistence of HIV-1 Structural Proteins and Glycoproteins in Lymph Nodes of Patients under Highly Active Antiretroviral Therapy","volume":"102","author":"Popovic","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pace, M.J., Graf, E.H., Agosto, L.M., Mexas, A.M., Male, F., Brady, T., Bushman, F.D., and O\u2019Doherty, U. (2012). Directly Infected Resting CD4+T Cells Can Produce HIV Gag without Spreading Infection in a Model of HIV Latency. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002818"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sun, N., and Yau, S.S.-T. (2022). In-Depth Investigation of the Point Mutation Pattern of HIV-1. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.1033481"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1007\/s13238-010-0068-0","article-title":"Dynamic Interplay between Viral Adaptation and Immune Recognition during HIV-1 Infection","volume":"1","author":"Motozono","year":"2010","journal-title":"Protein Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1097\/QAI.0000000000000164","article-title":"Detection of HIV-1 Matrix Protein P17 Quasispecies Variants in Plasma of Chronic HIV-1-Infected Patients by Ultra-Deep Pyrosequencing","volume":"66","author":"Giombini","year":"2014","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"001982","DOI":"10.1099\/jgv.0.001982","article-title":"Molecular Mechanisms behind the Generation of Pro-Oncogenic HIV-1 Matrix Protein P17 Variants","volume":"105","author":"Zani","year":"2024","journal-title":"J. Gen. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Giagulli, C., D\u2019Ursi, P., He, W., Zorzan, S., Caccuri, F., Varney, K., Orro, A., Marsico, S., Otjacques, B., and Laudanna, C. (2017). A Single Amino Acid Substitution Confers B-Cell Clonogenic Activity to the HIV-1 Matrix Protein P17. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-06848-y"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.bbagen.2018.09.016","article-title":"Identification of Amino Acid Residues Critical for the B Cell Growth-Promoting Activity of HIV-1 Matrix Protein P17 Variants","volume":"1863","author":"He","year":"2019","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41417-020-00246-9","article-title":"B-Cell Clonogenic Activity of HIV-1 P17 Variants Is Driven by PAR1-Mediated EGF Transactivation","volume":"28","author":"Giagulli","year":"2021","journal-title":"Cancer Gene Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"107334","DOI":"10.18632\/oncotarget.21015","article-title":"Protease-Activated Receptor-1 (PAR-1): A Promising Molecular Target for Cancer","volume":"8","author":"Liu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"D\u2019Ursi, P., Rondina, A., Zani, A., Uggeri, M., Messali, S., Caruso, A., and Caccuri, F. (2024). Molecular Mechanisms Involved in the B Cell Growth and Clonogenic Activity of HIV-1 Matrix Protein P17 Variants. Viruses, 16.","DOI":"10.3390\/v16071048"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14331","DOI":"10.1073\/pnas.1514748112","article-title":"Role of HIV-1 Matrix Protein P17 Variants in Lymphoma Pathogenesis","volume":"112","author":"Dolcetti","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1182\/blood-2011-06-364083","article-title":"HIV-1 Matrix Protein P17 Binds to the IL-8 Receptor CXCR1 and Shows IL-8-like Chemokine Activity on Monocytes through Rho\/ROCK Activation","volume":"119","author":"Giagulli","year":"2012","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13027-017-0160-7","article-title":"HIV-1 Matrix Protein P17 and Its Variants Promote Human Triple Negative Breast Cancer Cell Aggressiveness","volume":"12","author":"Caccuri","year":"2017","journal-title":"Infect. Agent. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14580","DOI":"10.1073\/pnas.1206605109","article-title":"HIV-1 Matrix Protein P17 Promotes Angiogenesis via Chemokine Receptors CXCR1 and CXCR2","volume":"109","author":"Caccuri","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1161\/ATVBAHA.113.302478","article-title":"HIV-1 Matrix Protein P17 Promotes Lymphangiogenesis and Activates the Endothelin-1\/Endothelin B Receptor Axis","volume":"34","author":"Caccuri","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"ftv062","DOI":"10.1093\/femspd\/ftv062","article-title":"Angiogenic, Lymphangiogenic and Adipogenic Effects of HIV-1 Matrix Protein P17","volume":"73","author":"Basta","year":"2015","journal-title":"Pathog. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1053\/sonc.2002.37263","article-title":"Role of Angiogenesis in Tumor Growth and Metastasis","volume":"29","author":"Folkman","year":"2002","journal-title":"Semin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"723","DOI":"10.2741\/3715","article-title":"Lymphangiogenesis and Cancer Metastasis","volume":"16","author":"Jiang","year":"2011","journal-title":"Front. Biosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/hon.2562","article-title":"Lymphomagenic Properties of a HIV P17 Variant Derived from a Splenic Marginal Zone Lymphoma Occurred in a HIV-Infected Patient","volume":"37","author":"Caccuri","year":"2019","journal-title":"Hematol. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2174\/156800908784293659","article-title":"The PTEN\/PI3K\/AKT Signalling Pathway in Cancer, Therapeutic Implications","volume":"8","author":"Carnero","year":"2008","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1002\/1878-0261.13500","article-title":"Activation of the EGFR\/PI3K\/AKT Pathway Limits the Efficacy of Trametinib Treatment in Head and Neck Cancer","volume":"17","author":"Novoplansky","year":"2023","journal-title":"Mol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/1469-0691.12056","article-title":"Next-Generation Sequencing Technology in Clinical Virology","volume":"19","author":"Capobianchi","year":"2013","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Perry, C., and Rayat, A.C.M.E. (2021). Lentiviral Vector Bioprocessing. Viruses, 13.","DOI":"10.3390\/v13020268"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"13168","DOI":"10.1073\/pnas.1615258113","article-title":"Expression of HIV-1 Matrix Protein P17 and Association with B-Cell Lymphoma in HIV-1 Transgenic Mice","volume":"113","author":"Carroll","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/cmdc.201200577","article-title":"Identification of a Small-Molecule Inhibitor of HIV-1 Assembly That Targets the Phosphatidylinositol (4,5)-Bisphosphate Binding Site of the HIV-1 Matrix Protein","volume":"8","author":"Zentner","year":"2013","journal-title":"ChemMedChem"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.vaccine.2013.12.051","article-title":"Synthetic HIV-1 Matrix Protein P17-Based AT20-KLH Therapeutic Immunization in HIV-1-Infected Patients Receiving Antiretroviral Treatment: A Phase I Safety and Immunogenicity Study","volume":"32","author":"Iaria","year":"2014","journal-title":"Vaccine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1179\/1528433614Z.0000000018","article-title":"Long-Lasting Humoral Immune Response Induced in HIV-1-Infected Patients by a Synthetic Peptide (AT20) Derived from the HIV-1 Matrix Protein P17 Functional Epitope","volume":"16","author":"Iaria","year":"2015","journal-title":"HIV Clin. Trials"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/4\/463\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:59:12Z","timestamp":1760029152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/4\/463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,24]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["v17040463"],"URL":"https:\/\/doi.org\/10.3390\/v17040463","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2025,3,24]]}}}