{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:17:54Z","timestamp":1793312274727,"version":"4.5.0"},"reference-count":119,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["25-15-00508"],"award-info":[{"award-number":["25-15-00508"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Nef is a non-structural regulatory protein of human immunodeficiency virus (HIV) that exerts pleiotropic effects on the immune system. In infected cells, Nef modulates the surface expression of molecules critical for immune responses and regulates cytokine production, vesicular trafficking, and lipid metabolism as well as apoptosis and autophagy. Despite significant improvements in antiretroviral therapy (ART), Nef is detected in the circulation of HIV-infected individuals as a soluble protein and in association with virions and extracellular vesicles, and it is regarded as a driver of a broad spectrum of HIV-associated comorbidities. Serum Nef concentrations range from a few to several tens of ng\/mL, comparable to systemic levels of certain proinflammatory cytokines in inflammatory diseases. This reflects the fact that the primary sources of Nef are cellular viral reservoirs in which ART does not suppress viral protein expression. Among these reservoirs, long-lived HIV-infected memory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and tissue-resident macrophages are considered the major contributors to systemic Nef production. Due to the need for a more comprehensive understanding of the\n                    <jats:italic>in vivo<\/jats:italic>\n                    functions of Nef and the molecular mechanisms by which it contributes to HIV-associated pathogenesis, a variety of mouse models expressing Nef were developed. This review summarizes existing transgenic mouse models with cell type-specific Nef expression and humanized mouse models used in HIV research, including models based on Nef-deficient strains. The development and systematic characterization of such models are essential for providing experimental validation for the clinical implementation of Nef inhibitors in combination with established ART.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1837301","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:53:32Z","timestamp":1785488012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Nef as a driver of immunodeficiency and HIV-associated diseases: insights from mouse models"],"prefix":"10.3389","volume":"17","author":[{"given":"A.S.","family":"Yakovleva","sequence":"first","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.A.","family":"Gorshkova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.O.","family":"Gubernatorova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.I.","family":"Bukrinsky","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.A.","family":"Nedospasov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University","place":["Moscow, Russia"]},{"name":"Sirius University of Science and Technology, Federal Territory Sirius","place":["Krasnodarsky krai, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.S.","family":"Drutskaya","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University","place":["Moscow, Russia"]},{"name":"Sirius University of Science and Technology, Federal Territory Sirius","place":["Krasnodarsky krai, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1097\/COH.0000000000000298","article-title":"Trends in life expectancy of HIV-positive adults on antiretroviral therapy across the globe: comparisons with general population","volume":"11","author":"Wandeler","year":"2016","journal-title":"Curr Opin HIV AIDS"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(24)00212-1","article-title":"Global, regional, and national burden of HIV\/AIDS, 1990\u20132021, and forecasts to 2050, for 204 countries and territories: the Global Burden of Disease Study 2021","volume":"11","author":"Carter","year":"2024","journal-title":"Lancet HIV"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081355","article-title":"Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada","volume":"8","author":"Samji","year":"2013","journal-title":"PloS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"15035","DOI":"10.1038\/nrdp.2015.35","article-title":"HIV infection","volume":"1","author":"Deeks","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.77509","article-title":"A comprehensive review of the manifestation of cardiovascular diseases in HIV patients","volume":"17","author":"Abarca","year":"2025","journal-title":"Cureus"},{"key":"B6","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/j.1749-6632.2001.tb03903.x","article-title":"Pathogenesis of HIV\u2010associated cardiomyopathy","volume":"946","author":"Barbaro","year":"2001","journal-title":"Ann N Y Acad Sci"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000526868","article-title":"HIV-associated nephropathy in 2022","volume":"3","author":"Rivera","year":"2022","journal-title":"Glomerular Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/s41572-023-00450-5","article-title":"HIV-associated lung disease","volume":"9","author":"Konstantinidis","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2025.1553594","article-title":"Nef is a key player in neuroinflammation and myelin impairment associated with neuroHIV","volume":"16","author":"Bukrinsky","year":"2025","journal-title":"Front Neurol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-017-8503-2","article-title":"HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment","volume":"264","author":"Eggers","year":"2017","journal-title":"J Neurol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.945956","article-title":"The reservoir of latent HIV","volume":"12","author":"Chen","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/v16091484","article-title":"New therapies and strategies to curb HIV infections with a focus on macrophages and reservoirs","volume":"16","author":"Marra","year":"2024","journal-title":"Viruses"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13112629","article-title":"HIV therapy: the latest developments in antiviral drugs\u2014a scoping review","volume":"13","author":"Fanjul","year":"2025","journal-title":"Biomedicines"},{"key":"B14","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1146\/annurev.immunol.18.1.665","article-title":"Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy","volume":"18","author":"Pierson","year":"2000","journal-title":"Annu Rev Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199501263320405","article-title":"Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection","volume":"332","author":"Kirchhoff","year":"1995","journal-title":"N Engl J Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5238.988","article-title":"Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients","volume":"270","author":"Deacon","year":"1995","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1917876117","article-title":"Defective HIV-1 proviruses produce viral proteins","volume":"117","author":"Imamichi","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI154422","article-title":"The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells","volume":"132","author":"Duette","year":"2022","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2018-0089OC","article-title":"HIV-Nef protein persists in the lungs of aviremic patients with HIV and induces endothelial cell death","volume":"60","author":"Chelvanambi","year":"2019","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/v14122774","article-title":"The persistence of HIV diversity, transcription, and Nef protein in Kaposi\u2019s sarcoma tumors during antiretroviral therapy","volume":"14","author":"Nolan","year":"2022","journal-title":"Viruses"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.11.8833-8840.1998","article-title":"Virion incorporation of human immunodeficiency virus type 1 Nef is mediated by a bipartite membrane-targeting signal: analysis of its role in enhancement of viral infectivity","volume":"72","author":"Welker","year":"1998","journal-title":"J Virol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191613","article-title":"Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA","volume":"13","author":"Ferdin","year":"2018","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-7-77","article-title":"Self-association of the lentivirus protein, nef","volume":"7","author":"Kwak","year":"2010","journal-title":"Retrovirology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02344-17","article-title":"Nef secretion into extracellular vesicles or exosomes is conserved across human and simian immunodeficiency viruses","volume":"9","author":"McNamara","year":"2018","journal-title":"mBio"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2009.0170","article-title":"HIV type 1 Nef is released from infected cells in CD45+ microvesicles and is present in the plasma of HIV-infected individuals","volume":"27","author":"Raymond","year":"2011","journal-title":"AIDS Res Hum Retroviruses"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.03.004","article-title":"HIV-Nef and ADAM17-containing plasma extracellular vesicles induce and correlate with immune pathogenesis in chronic HIV infection","volume":"6","author":"Lee","year":"2016","journal-title":"EBioMedicine"},{"key":"B27","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/34929","article-title":"HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes","volume":"391","author":"Collins","year":"1998","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221256498","article-title":"HIV-1 Nef impairs MHC class II antigen presentation and surface expression","volume":"98","author":"Stumptner-Cuvelette","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/350508a0","article-title":"Serine phosphorylation-independent downregulation of cell-surface CD4 by nef","volume":"350","author":"Garcia","year":"1991","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.7.1593","article-title":"Mechanism for down-regulation of CD28 by nef","volume":"20","author":"Swigut","year":"2001","journal-title":"EMBO J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1725401","article-title":"HIV-1 Nef counteracts autophagy restriction by enhancing the association between BECN1 and its inhibitor BCL2 in a PRKN-dependent manner","volume":"17","author":"Castro-Gonzalez","year":"2021","journal-title":"Autophagy"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2010.77","article-title":"Mechanisms of HIV-associated lymphocyte apoptosis: 2010","volume":"1","author":"Cummins","year":"2010","journal-title":"Cell Death Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1086\/654817","article-title":"Circulating Nef induces dyslipidemia in simian immunodeficiency virus\u2013infected macaques by suppressing cholesterol efflux","volume":"202","author":"Asztalos","year":"2010","journal-title":"J Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1437453100","article-title":"Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions","volume":"100","author":"Zheng","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0040365","article-title":"Human immunodeficiency virus impairs reverse cholesterol transport from macrophages","volume":"4","author":"Mujawar","year":"2006","journal-title":"PloS Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.7.3178","article-title":"Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium\/calmodulin-dependent phosphodiesterase signal transduction pathway","volume":"94","author":"Brigino","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"B37","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/12433","article-title":"HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages","volume":"5","author":"Swingler","year":"1999","journal-title":"Nat Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.12.5326","article-title":"Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA","volume":"88","author":"Luria","year":"1991","journal-title":"Proc Natl Acad Sci USA"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.05.188","article-title":"HIV-1 Nef promotes ubiquitination and proteasomal degradation of p53 tumor suppressor protein by using E6AP","volume":"529","author":"Ali","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"B40","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13027-020-00320-9","article-title":"HIV Nef enhances the expression of oncogenic c-MYC and activation-induced cytidine deaminase in Burkitt lymphoma cells, promoting genomic instability","volume":"15","author":"Mdletshe","year":"2020","journal-title":"Infect Agents Cancer"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku583","article-title":"HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN\/AKT\/mTOR signaling pathway","volume":"42","author":"Xue","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111674","article-title":"Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells","volume":"41","author":"Dubrovsky","year":"2022","journal-title":"Cell Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007907","article-title":"Exosomes containing HIV protein Nef reorganize lipid rafts potentiating inflammatory response in bystander cells","volume":"15","author":"Mukhamedova","year":"2019","journal-title":"PloS Pathog"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.233","article-title":"Macropinocytosis and TAK1 mediate anti-inflammatory to pro-inflammatory macrophage differentiation by HIV-1 Nef","volume":"5","author":"Hashimoto","year":"2014","journal-title":"Cell Death Dis"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/v14092025","article-title":"Antiretroviral drug discovery targeting the HIV-1 Nef virulence factor","volume":"14","author":"Emert-Sedlak","year":"2022","journal-title":"Viruses"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81276-3","article-title":"Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain","volume":"85","author":"Lee","year":"1996","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-11-24","article-title":"Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody","volume":"11","author":"L\u00fclf","year":"2014","journal-title":"Retrovirology"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2013.07.002","article-title":"Small molecule inhibitors of the HIV-1 virulence factor, Nef","volume":"10","author":"Smithgall","year":"2013","journal-title":"Drug Discov Today: Technol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.9b00382","article-title":"Tight-binding hydroxypyrazole HIV-1 Nef inhibitors suppress viral replication in donor mononuclear cells and reverse Nef-mediated MHC-I downregulation","volume":"6","author":"Shi","year":"2020","journal-title":"ACS Infect Dis"},{"key":"B50","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1021\/acsinfecdis.1c00288","article-title":"Inhibitors of HIV-1 Nef-mediated activation of the myeloid Src-family kinase Hck block HIV-1 replication in macrophages and disrupt MHC-I downregulation","volume":"8","author":"Emert-Sedlak","year":"2022","journal-title":"ACS Infect Dis"},{"key":"B51","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.chembiol.2024.02.004","article-title":"PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication","volume":"31","author":"Emert-Sedlak","year":"2024","journal-title":"Cell Chem Biol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.09.047","article-title":"HIV-1 Nef dimerization is required for Nef-mediated receptor downregulation and viral replication","volume":"394","author":"Poe","year":"2009","journal-title":"J Mol Biol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000001951","article-title":"Modelling interaction between HIV-1 Nef and calnexin","volume":"32","author":"Adzhubei","year":"2018","journal-title":"AIDS"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.116.307997","article-title":"Interaction between HIV-1 Nef and calnexin: From modeling to small molecule inhibitors reversing HIV-induced lipid accumulation","volume":"36","author":"Hunegnaw","year":"2016","journal-title":"ATVB"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12478","article-title":"HIV\u20101 Nef is carried on the surface of extracellular vesicles","volume":"13","author":"Vanpouille","year":"2024","journal-title":"J Extracellular Vesicle"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-011-9262-y","article-title":"Mechanisms of HIV-1 Nef function and intracellular signaling","volume":"6","author":"Foster","year":"2011","journal-title":"J Neuroimmune Pharmacol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msad101","article-title":"Genomic evidence for the nonpathogenic state in HIV-1\u2013infected Northern pig-tailed macaques","volume":"40","author":"Pang","year":"2023","journal-title":"Mol Biol Evol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(00)01816-3","article-title":"The chimpanzee and other non-human-primate models in HIV-1 vaccine research","volume":"8","author":"Nath","year":"2000","journal-title":"Trends Microbiol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2020.07.014","article-title":"Extracellular vesicles in virus infection and pathogenesis","volume":"44","author":"McNamara","year":"2020","journal-title":"Curr Opin Virol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/301527a0","article-title":"A severe combined immunodeficiency mutation in the mouse","volume":"301","author":"Bosma","year":"1983","journal-title":"Nature"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1126\/science.241.4873.1632","article-title":"The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function","volume":"241","author":"McCune","year":"1988","journal-title":"Science"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.6.3478-3485.1994","article-title":"Requirement of human immunodeficiency virus type 1 nef for in vivo replication and pathogenicity","volume":"68","author":"Jamieson","year":"1994","journal-title":"J Virol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.5.4161-4164.1997","article-title":"Deletion of nef slows but does not prevent CD4-positive T-cell depletion in human immunodeficiency virus type 1-infected human-PBL-SCID mice","volume":"71","author":"Gulizia","year":"1997","journal-title":"J Virol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-9-44","article-title":"Nef functions in BLT mice to enhance HIV-1 replication and deplete CD4+CD8+ thymocytes","volume":"9","author":"Zou","year":"2012","journal-title":"Retrovirology"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2024.110192","article-title":"Nef defect attenuates HIV viremia and immune dysregulation in the bone marrow-liver-thymus-spleen (BLTS) humanized mouse model","volume":"598","author":"Biradar","year":"2024","journal-title":"Virology"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00485-08","article-title":"Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism","volume":"82","author":"Muthumani","year":"2008","journal-title":"J Virol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.70266","article-title":"Humanizing mice for human immunodeficiency virus infection studies","volume":"5","author":"Roy","year":"2025","journal-title":"Curr Protocol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaf192","article-title":"Increased atherosclerosis in HIV-infected humanized mice is caused by a single viral protein, Nef","volume":"232","author":"Wang","year":"2025","journal-title":"J Infect Dis"},{"key":"B69","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s13062-021-00317-3","article-title":"HIV-1LAI Nef blocks the development of hematopoietic stem\/progenitor cells into myeloid-erythroid lineage cells","volume":"16","author":"Zou","year":"2021","journal-title":"Biol Direct"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000002837","article-title":"HIV-1LAI Nef blocks the development of hematopoietic stem\/progenitor cells into T lymphoid cells","volume":"35","author":"Zou","year":"2021","journal-title":"AIDS"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0b013e32834086b3","article-title":"Hematopoietic stem\/precursor cells as HIV reservoirs","volume":"6","author":"McNamara","year":"2011","journal-title":"Curr Opin HIV AIDS"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00060","article-title":"Hematopoietic stem\/progenitor cells and the pathogenesis of HIV\/AIDS","volume":"10","author":"Tsukamoto","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"key":"B73","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1084\/jem.179.3.797","article-title":"Severe immunodeficiency associated with a human immunodeficiency virus 1 NEF\/3\u2019-long terminal repeat transgene","volume":"179","author":"Lindemann","year":"1994","journal-title":"J Exp Med"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1993.tb05704.x","article-title":"Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene","volume":"12","author":"Skowronski","year":"1993","journal-title":"EMBO J"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1993.tb06186.x","article-title":"CD4 cell surface downregulation in HIV-1 Nef transgenic mice is a consequence of intracellular sequestration","volume":"12","author":"Brady","year":"1993","journal-title":"EMBO J"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.1.121-132.1998","article-title":"Transgenic mice expressing human immunodeficiency virus type 1 in immune cells develop a severe AIDS-like disease","volume":"72","author":"Hanna","year":"1998","journal-title":"J Virol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.21.11733-11744.2003","article-title":"The AIDS-like disease of CD4C\/human immunodeficiency virus transgenic mice is associated with accumulation of immature CD11bHi dendritic cells","volume":"77","author":"Poudrier","year":"2003","journal-title":"J Virol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.19.9378-9392.2001","article-title":"The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C\/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck","volume":"75","author":"Hanna","year":"2001","journal-title":"J Virol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.8.3981-3995.2002","article-title":"Expression of simian immunodeficiency virus nef in immune cells of transgenic mice leads to a severe AIDS-like disease","volume":"76","author":"Simard","year":"2002","journal-title":"J Virol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.10.8371-8383.1999","article-title":"The human immunodeficiency virus type 1 nef gene can to a large extent replace simian immunodeficiency virus nef in vivo","volume":"73","author":"Kirchhoff","year":"1999","journal-title":"J Virol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1994.1303","article-title":"Specific suppression of human CD4 surface expression by Nef from the pathogenic simian immunodeficiency virus SIVmac239open","volume":"201","author":"Foster","year":"1994","journal-title":"Virology"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01466-09","article-title":"Adult AIDS-like disease in a novel inducible human immunodeficiency virus type 1 Nef transgenic mouse model: CD4+ T-cell activation is Nef dependent and can occur in the absence of lymphophenia","volume":"83","author":"Rahim","year":"2009","journal-title":"J Virol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00125-09","article-title":"Selective expression of human immunodeficiency virus Nef in specific immune cell populations of transgenic mice is associated with distinct AIDS-like phenotypes","volume":"83","author":"Hanna","year":"2009","journal-title":"J Virol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00471-21","article-title":"HIV-1 Nef induces Hck\/Lyn-dependent expansion of myeloid-derived suppressor cells associated with elevated interleukin-17\/G-CSF levels","volume":"95","author":"Priceputu","year":"2021","journal-title":"J Virol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.10.6560","article-title":"Functional analysis of HIV type 1 Nef reveals a role for PAK2 as a regulator of cell phenotype and function in the murine dendritic cell line, DC2.4","volume":"175","author":"Mann","year":"2005","journal-title":"J Immunol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2016.66","article-title":"New roles for CD14 and IL\u2010\u03b2 linking inflammatory dendritic cells to IL\u201017 production in memory CD4+ T cells","volume":"94","author":"Ilarregui","year":"2016","journal-title":"Immunol Cell Biol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"13343","DOI":"10.1038\/s41598-020-70231-7","article-title":"Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas","volume":"10","author":"Dawod","year":"2020","journal-title":"Sci Rep"},{"key":"B88","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.bbi.2014.02.016","article-title":"HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors","volume":"40","author":"Acharjee","year":"2014","journal-title":"Brain Behavior Immun"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02447","article-title":"Nef-induced CCL2 expression contributes to HIV\/SIV brain invasion and neuronal dysfunction","volume":"10","author":"Lehmann","year":"2019","journal-title":"Front Immunol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091063","article-title":"Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction","volume":"9","author":"Wang","year":"2014","journal-title":"PloS One"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1177\/0003319710364215","article-title":"The role of ERK1\/2 signaling pathway in Nef protein upregulation of the expression of the intercellular adhesion molecule 1 in endothelial cells","volume":"61","author":"Fan","year":"2010","journal-title":"Angiology"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03231","article-title":"HIV-1 Nef upregulates CCL2\/MCP-1 expression in astrocytes in a myristoylation- and calmodulin-dependent manner","volume":"119","author":"Lehmann","year":"2006","journal-title":"J Cell Sci"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.21.11745-11753.2003","article-title":"Oligodendrocyte-specific expression of human immunodeficiency virus type 1 Nef in transgenic mice leads to vacuolar myelopathy and alters oligodendrocyte phenotype in vitro","volume":"77","author":"Radja","year":"2003","journal-title":"J Virol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci6030023","article-title":"Oligodendrocyte injury and pathogenesis of HIV-1-associated neurocognitive disorders","volume":"6","author":"Liu","year":"2016","journal-title":"Brain Sci"},{"key":"B95","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1186\/s12974-024-03124-5","article-title":"Extracellular vesicles produced by HIV-1 Nef-expressing cells induce myelin impairment and oligodendrocyte damage in the mouse central nervous system","volume":"21","author":"Schenck","year":"2024","journal-title":"J Neuroinflamm"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.3390\/biom16020332","article-title":"ABCA1: A therapeutic target for improving cholesterol homeostasis in peripheral neuropathies","volume":"16","author":"Woo","year":"2026","journal-title":"Biomolecules"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(91)90759-5","article-title":"HIV-associated nephropathy in transgenic mice expressing HIV-1 genes","volume":"185","author":"Dickie","year":"1991","journal-title":"Virology"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1097\/01.aids.0000191918.42110.27","article-title":"HIV-1 Nef induces dedifferentiation of podocytes in vivo: a characteristic feature of HIVAN","volume":"19","author":"Husain","year":"2005","journal-title":"AIDS"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1038\/nm0502-522","article-title":"Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy","volume":"8","author":"Marras","year":"2002","journal-title":"Nat Med"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V11112079","article-title":"Renal epithelium is a previously unrecognized site of HIV-1 infection","volume":"11","author":"Bruggeman","year":"2000","journal-title":"J Am Soc Nephrol"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200421004","article-title":"Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways","volume":"114","author":"He","year":"2004","journal-title":"J Clin Invest"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252111401","article-title":"HIV protein Nef induces cardiomyopathy through induction of Bcl2 and p21","volume":"25","author":"Kondrachuk","year":"2024","journal-title":"IJMS"},{"key":"B103","doi-asserted-by":"publisher","first-page":"8572","DOI":"10.1038\/s41598-017-08736-x","article-title":"HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy","volume":"7","author":"Gupta","year":"2017","journal-title":"Sci Rep"},{"key":"B104","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1089\/aid.2016.0128","article-title":"Short communication: Accumulation of neutral lipids in liver and aorta of Nef-transgenic mice","volume":"33","author":"Pushkarsky","year":"2017","journal-title":"AIDS Res Hum Retroviruses"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.583591","article-title":"HIV-1 protein Nef inhibits activity of ATP-binding cassette transporter A1 by targeting endoplasmic reticulum chaperone calnexin","volume":"289","author":"Jennelle","year":"2014","journal-title":"J Biol Chem"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.315082","article-title":"HIV-Nef protein transfer to endothelial cells requires Rac1 activation and leads to endothelial dysfunction implications for statin treatment in HIV patients","volume":"125","author":"Chelvanambi","year":"2019","journal-title":"Circ Res"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1993.1607","article-title":"Spontaneous and inducible epidermal hyperplasia in transgenic mice expressing HIV-1 Nef","volume":"197","author":"Dickie","year":"1993","journal-title":"Virology"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114849","article-title":"In vivo activation by ultraviolet rays of the human immunodeficiency virus type 1 long terminal repeat","volume":"86","author":"Cavard","year":"1990","journal-title":"J Clin Invest"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023442","article-title":"Exogenous HIV-1 Nef upsets the IFN-\u03b3-induced impairment of human intestinal epithelial integrity","volume":"6","author":"Quaranta","year":"2011","journal-title":"PloS One"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0500649102","article-title":"A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness","volume":"102","author":"Potash","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007061","article-title":"EcoHIV infection of mice establishes latent viral reservoirs in T cells and active viral reservoirs in macrophages that are sufficient for induction of neurocognitive impairment","volume":"14","author":"Gu","year":"2018","journal-title":"PloS Pathog"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202402879","article-title":"Nef mediates neuroimmune response, myelin impairment, and neuronal injury in EcoHIV-infected mice","volume":"8","author":"Schenck","year":"2025","journal-title":"Life Sci Alliance"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.3390\/cells11101599","article-title":"Recent advances in the molecular and cellular mechanisms of gp120-mediated neurotoxicity","volume":"11","author":"Avdoshina","year":"2022","journal-title":"Cells"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04173-w","article-title":"Transactivator of transcription (Tat)-induced neuroinflammation as a key pathway in neuronal dysfunction: A scoping review","volume":"61","author":"Muvenda","year":"2024","journal-title":"Mol Neurobiol"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00185","article-title":"HIV proteins and endothelial dysfunction: Implications in cardiovascular disease","volume":"5","author":"Anand","year":"2018","journal-title":"Front Cardiovasc Med"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000400","article-title":"Changing concepts of HIV infection and renal disease","volume":"27","author":"Hou","year":"2018","journal-title":"Curr Opin Nephrol Hypertension"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.3390\/cimb47050367","article-title":"Mechanisms of immune evasion in HIV-1: The role of virus-host protein interactions","volume":"47","author":"Mouzakis","year":"2025","journal-title":"Curr Issues Mol Biol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e10-05-0470","article-title":"Small molecule inhibition of HIV-1\u2013induced MHC-I down-regulation identifies a temporally regulated switch in Nef action","volume":"21","author":"Dikeakos","year":"2010","journal-title":"MBoC"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-10-135","article-title":"Discovery of a diaminoquinoxaline benzenesulfonamide antagonist of HIV-1 Nef function using a yeast-based phenotypic screen","volume":"10","author":"Trible","year":"2013","journal-title":"Retrovirology"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1837301\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:53:34Z","timestamp":1785488014000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1837301\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":119,"alternative-id":["10.3389\/fimmu.2026.1837301"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1837301","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]},"article-number":"1837301"}}