{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T20:32:38Z","timestamp":1786825958129,"version":"build-2736575974"},"reference-count":66,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institutes Health","doi-asserted-by":"publisher","award":["AI152677"],"award-info":[{"award-number":["AI152677"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institutes Health","doi-asserted-by":"publisher","award":["AI057083"],"award-info":[{"award-number":["AI057083"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institutes Health","doi-asserted-by":"publisher","award":["AI102724"],"award-info":[{"award-number":["AI102724"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institutes Health","doi-asserted-by":"publisher","award":["GM112516"],"award-info":[{"award-number":["GM112516"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>While antiretroviral drugs have transformed the lives of HIV-infected individuals, chronic treatment is required to prevent rebound from viral reservoir cells. People living with HIV also are at higher risk for cardiovascular and neurocognitive complications, as well as cancer. Finding a cure for HIV-1 infection is therefore an essential goal of current AIDS research. This review is focused on the discovery of pharmacological inhibitors of the HIV-1 Nef accessory protein. Nef is well known to enhance HIV-1 infectivity and replication, and to promote immune escape of HIV-infected cells by preventing cell surface MHC-I display of HIV-1 antigens. Recent progress shows that Nef inhibitors not only suppress HIV-1 replication, but also restore sufficient MHC-I to the surface of infected cells to trigger a cytotoxic T lymphocyte response. Combining Nef inhibitors with latency reversal agents and therapeutic vaccines may provide a path to clearance of viral reservoirs.<\/jats:p>","DOI":"10.3390\/v14092025","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:15:02Z","timestamp":1663114502000},"page":"2025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Antiretroviral Drug Discovery Targeting the HIV-1 Nef Virulence Factor"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8123-7891","authenticated-orcid":false,"given":"Lori A.","family":"Emert-Sedlak","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibin","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin M.","family":"Tice","sequence":"additional","affiliation":[{"name":"Fox Chase Chemical Diversity Center, Inc., Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry T.","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4305-5699","authenticated-orcid":false,"given":"Shoucheng","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0645-4209","authenticated-orcid":false,"given":"Catherine E.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay E.","family":"Wrobel","sequence":"additional","affiliation":[{"name":"Fox Chase Chemical Diversity Center, Inc., Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen B.","family":"Reitz","sequence":"additional","affiliation":[{"name":"Fox Chase Chemical Diversity Center, Inc., Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5238-3806","authenticated-orcid":false,"given":"Thomas E.","family":"Smithgall","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.idc.2019.05.006","article-title":"Key Principles of Antiretroviral Pharmacology","volume":"33","author":"Dionne","year":"2019","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1056\/NEJMoa0908492","article-title":"Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand","volume":"361","author":"Pitisuttithum","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.chom.2017.12.004","article-title":"Getting the \u201cKill\u201d into \u201cShock and Kill\u201d: Strategies to Eliminate Latent HIV","volume":"23","author":"Kim","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/s41586-020-1946-0","article-title":"Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8(+) cells","volume":"578","author":"McBrien","year":"2020","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41586-020-1951-3","article-title":"Systemic HIV and SIV latency reversal via non-canonical NF-kappaB signalling in vivo","volume":"578","author":"Nixon","year":"2020","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1006\/jmbi.1999.2740","article-title":"Structure of the anchor-domain of myristoylated and non-myristoylated HIV-1 Nef protein","volume":"289","author":"Geyer","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nchembio.268","article-title":"HIV-1 Nef membrane association depends on charge, curvature, composition and sequence","volume":"6","author":"Gerlach","year":"2010","journal-title":"Nat. Chem. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1016\/j.str.2013.08.008","article-title":"Conformational transition of membrane-associated terminally acylated HIV-1 Nef","volume":"21","author":"Akgun","year":"2013","journal-title":"Structure"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1016\/j.bpj.2010.07.016","article-title":"Neutron reflectometry study of the conformation of HIV Nef bound to lipid membranes","volume":"99","author":"Kent","year":"2010","journal-title":"Biophys. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.bbagen.2015.01.003","article-title":"HIV-1 Nef: A master manipulator of the membrane trafficking machinery mediating immune evasion","volume":"1850","author":"Pawlak","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"490","DOI":"10.2174\/157016211798842125","article-title":"Role of the CD4 down-modulation activity of Nef in HIV-1 infectivity","volume":"9","author":"Doria","year":"2011","journal-title":"Curr. HIV Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nature15399","article-title":"HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation","volume":"526","author":"Rosa","year":"2015","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nature15400","article-title":"SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef","volume":"526","author":"Usami","year":"2015","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1128\/JVI.02477-12","article-title":"Comparative proteomic analysis of HIV-1 particles reveals a role for Ezrin and EHD4 in the Nef-dependent increase of virus infectivity","volume":"87","author":"Bregnard","year":"2013","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S1097-2765(01)80005-8","article-title":"Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions","volume":"3","author":"Fackler","year":"1999","journal-title":"Mol. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15158","DOI":"10.1074\/jbc.REV120.012317","article-title":"Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes","volume":"295","author":"Staudt","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/0092-8674(91)90097-I","article-title":"Importance of the nef gene for maintenance of high viral loads and for development of AIDS","volume":"65","author":"Kestler","year":"1991","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"228","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":"ref_19","doi-asserted-by":"crossref","first-page":"988","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":"ref_20","doi-asserted-by":"crossref","first-page":"44","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":"ref_21","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12977-015-0187-z","article-title":"In vivo analysis of Nef\u2019s role in HIV-1 replication, systemic T cell activation and CD4(+) T cell loss","volume":"12","author":"Watkins","year":"2015","journal-title":"Retrovirology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1093\/embo-reports\/kve141","article-title":"Structure\u2014Function relationships in HIV-1 Nef","volume":"2","author":"Geyer","year":"2001","journal-title":"EMBO Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"531","DOI":"10.2174\/157016211798842107","article-title":"Interactions of the HIV\/SIV pathogenicity factor Nef with SH3 domain-containing host cell proteins","volume":"9","author":"Saksela","year":"2011","journal-title":"Curr. HIV Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/j.1460-2075.1995.tb07024.x","article-title":"Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down-regulation of CD4","volume":"14","author":"Saksela","year":"1995","journal-title":"EMBO J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"931","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":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhao, Z., Fagerlund, R., Tossavainen, H., Hopfensperger, K., Lotke, R., Srinivasachar Badarinarayan, S., Kirchhoff, F., Permi, P., Sato, K., and Sauter, D. (2021). Evolutionary plasticity of SH3 domain binding by Nef proteins of the HIV-1\/SIVcpz lentiviral lineage. PLoS Pathog., 17.","DOI":"10.1101\/2021.06.22.449400"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19256","DOI":"10.1073\/pnas.0707130104","article-title":"Protein protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein","volume":"104","author":"Betzi","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nsmb.2328","article-title":"Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef","volume":"19","author":"Jia","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7401","DOI":"10.1016\/j.bmc.2011.10.051","article-title":"A specific protein disorder catalyzer of HIV-1 Nef","volume":"19","author":"Lugari","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1684\/vir.2022.0940","article-title":"Inhibitors of HIV-1 Nef: Applications and developments for a practical cure","volume":"26","author":"Lurie","year":"2022","journal-title":"Virologie"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1091\/mbc.e10-05-0470","article-title":"Small molecule inhibition of HIV-1-induced MHC-I down-regulation identifies a temporally regulated switch in Nef action","volume":"21","author":"Dikeakos","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.3389\/fimmu.2019.02151","article-title":"Lovastatin Inhibits HIV-1-Induced MHC-I Downregulation by Targeting Nef-AP-1 Complex Formation: A New Strategy to Boost Immune Eradication of HIV-1 Infected Cells","volume":"10","author":"Liu","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"23835","DOI":"10.1073\/pnas.2008615117","article-title":"Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes","volume":"117","author":"Painter","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1021\/cb900195c","article-title":"Chemical library screens targeting an HIV-1 accessory factor\/host cell kinase complex identify novel antiretroviral compounds","volume":"4","author":"Kodama","year":"2009","journal-title":"ACS Chem. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.chembiol.2012.11.005","article-title":"Effector Kinase Coupling Enables High-Throughput Screens for Direct HIV-1 Nef Antagonists with Antiretroviral Activity","volume":"20","author":"Narute","year":"2013","journal-title":"Chem. Biol."},{"key":"ref_36","first-page":"e93684","article-title":"Pharmacologic HIV-1 Nef Blockade Enhances the Recognition and Elimination of Latently HIV-1 Infected CD4 T cells by Autologous CD8 T cells","volume":"2","author":"Mujib","year":"2017","journal-title":"J. Clin. Investig. Insight"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/j.bmcl.2016.01.043","article-title":"Synthesis and evaluation of orally active small molecule HIV-1 Nef antagonists","volume":"26","author":"Loughran","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","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":"Shi","year":"2022","journal-title":"ACS Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10","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":"ref_40","doi-asserted-by":"crossref","first-page":"135","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"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e154422","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. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e01832","DOI":"10.1128\/JVI.01832-18","article-title":"HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals","volume":"93","author":"Omondi","year":"2019","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11772","DOI":"10.1074\/jbc.M707572200","article-title":"HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) down-regulation: Analysis using short interfering RNA and knock-out mice","volume":"283","author":"Atkins","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.chom.2007.03.004","article-title":"HIV-1 Nef assembles a Src family kinase-ZAP-70\/Syk-PI3K cascade to downregulate cell-surface MHC-I","volume":"1","author":"Hung","year":"2007","journal-title":"Cell Host Microbe"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12840","DOI":"10.1074\/jbc.M413538200","article-title":"HIV-1 Nef disrupts antigen presentation early in the secretory pathway","volume":"280","author":"Kasper","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/tra.12412","article-title":"HIV-1 Nef: Taking Control of Protein Trafficking","volume":"17","author":"Pereira","year":"2016","journal-title":"Traffic"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1038\/sj.onc.1205271","article-title":"UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug","volume":"21","author":"Oneyama","year":"2002","journal-title":"Oncogene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S1074-5521(03)00101-7","article-title":"Synthetic inhibitors of proline-rich ligand-mediated protein-protein interaction: Potent analogs of UCS15A","volume":"10","author":"Oneyama","year":"2003","journal-title":"Chem. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27029","DOI":"10.1074\/jbc.M601128200","article-title":"HIV-1 Nef selectively activates SRC family kinases HCK, LYN, and c-SRC through direct SH3 domain interaction","volume":"281","author":"Trible","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Chutiwitoonchai, N., Hiyoshi, M., Mwimanzi, P., Ueno, T., Adachi, A., Ode, H., Sato, H., Fackler, O.T., Okada, S., and Suzu, S. (2011). The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027696"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jinf.2012.10.016","article-title":"Randomized clinical trial of lovastatin in HIV-infected, HAART naive patients (NCT00721305)","volume":"65","author":"Montoya","year":"2012","journal-title":"J. Infect."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.ejcb.2008.03.008","article-title":"Hematopoietic cell kinase (Hck) isoforms and phagocyte duties\u2014From signaling and actin reorganization to migration and phagocytosis","volume":"87","author":"Guiet","year":"2008","journal-title":"Eur. J. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1084\/jem.20022018","article-title":"CSF-induced and HIV-1-mediated distinct regulation of Hck and C\/EBPbeta represent a heterogeneous susceptibility of monocyte-derived macrophages to M-tropic HIV-1 infection","volume":"198","author":"Komuro","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1007\/s00018-008-8122-2","article-title":"Structure and dynamic regulation of Src-family kinases","volume":"65","author":"Engen","year":"2008","journal-title":"Cell Mol. Life Sci"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7918","DOI":"10.1038\/sj.onc.1208081","article-title":"Structure and regulation of Src family kinases","volume":"23","author":"Boggon","year":"2004","journal-title":"Oncogene"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/385650a0","article-title":"Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement","volume":"385","author":"Moarefi","year":"1997","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"17899","DOI":"10.1074\/jbc.272.29.17899","article-title":"SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1","volume":"272","author":"Briggs","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1021\/acs.biochem.5b00875","article-title":"Subtle Dynamic Changes Accompany Hck Activation by HIV-1 Nef and are Reversed by an Antiretroviral Kinase Inhibitor","volume":"54","author":"Wales","year":"2015","journal-title":"Biochemistry"},{"key":"ref_59","first-page":"365","article-title":"SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo","volume":"9","author":"Lerner","year":"2002","journal-title":"Nat. Struct. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Narute, P.S., and Smithgall, T.E. (2012). Nef alleles from all major HIV-1 clades activate Src-family kinases and enhance HIV-1 replication in an inhibitor-sensitive manner. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032561"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.jim.2015.08.010","article-title":"A robust and scalable TCR-based reporter cell assay to measure HIV-1 Nef-mediated T cell immune evasion","volume":"426","author":"Anmole","year":"2015","journal-title":"J. Immunol. Methods"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"28539","DOI":"10.1074\/jbc.M114.600031","article-title":"Interaction with the Src homology (SH3-SH2) region of the Src-family kinase Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment","volume":"289","author":"Alvarado","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/s41594-020-0463-z","article-title":"Structural basis of CD4 downregulation by HIV-1 Nef","volume":"27","author":"Kwon","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.jmb.2017.12.008","article-title":"Remodeling of HIV-1 Nef Structure by Src-Family Kinase Binding","volume":"430","author":"Moroco","year":"2018","journal-title":"J. Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1177\/1087057113513640","article-title":"Development and Validation of a High-Content Bimolecular Fluorescence Complementation Assay for Small-Molecule Inhibitors of HIV-1 Nef Dimerization","volume":"19","author":"Poe","year":"2014","journal-title":"J. Biomol. Screen"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1146\/annurev-biophys-051013-022846","article-title":"Split Green Fluorescent Proteins: Scope, Limitations, and Outlook","volume":"48","author":"Romei","year":"2019","journal-title":"Annu. Rev. Biophys."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/2025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:30:22Z","timestamp":1760142622000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,13]]},"references-count":66,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["v14092025"],"URL":"https:\/\/doi.org\/10.3390\/v14092025","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,13]]}}}