{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:51:54Z","timestamp":1762102314319,"version":"build-2065373602"},"reference-count":104,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T00:00:00Z","timestamp":1543536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["HIG-133050"],"award-info":[{"award-number":["HIG-133050"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Finding a cure for HIV is challenging because the virus is able to integrate itself into the host cell genome and establish a silent state, called latency, allowing it to evade antiviral drugs and the immune system. Various \u201cshock and kill\u201d strategies are being explored in attempts to eliminate latent HIV reservoirs. The goal of these approaches is to reactivate latent viruses (\u201cshock\u201d), thereby exposing them to clearance by viral cytopathic effects or immune-mediated responses (\u201ckill\u201d). To date, there has been limited clinical success using these methods. In this review, we highlight various functions of the HIV accessory protein Nef and discuss their double-edged effects that may contribute to the limited effectiveness of current \u201cshock and kill\u201d methods to eradicate latent HIV reservoirs in treated individuals.<\/jats:p>","DOI":"10.3390\/v10120677","type":"journal-article","created":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T12:13:17Z","timestamp":1543579997000},"page":"677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Implications of HIV-1 Nef for \u201cShock and Kill\u201d Strategies to Eliminate Latent Viral Reservoirs"],"prefix":"10.3390","volume":"10","author":[{"given":"Xiaomei T.","family":"Kuang","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6432-1426","authenticated-orcid":false,"given":"Mark A.","family":"Brockman","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada"},{"name":"Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada"},{"name":"British Columbia Centre for Excellence in HIV\/AIDS, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1056\/NEJMoa0802905","article-title":"Long-term control of HIV by CCR5 Delta32\/Delta32 stem-cell transplantation","volume":"360","author":"Hutter","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yukl, S.A., Boritz, E., Busch, M., Bentsen, C., Chun, T.W., Douek, D., Eisele, E., Haase, A., Ho, Y.C., and Hutter, G. (2013). Challenges in detecting HIV persistence during potentially curative interventions: A study of the Berlin patient. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003347"},{"key":"ref_3","unstructured":"UNAIDS\/WHO (2018). Global HIV & AIDS Statistics\u20142018 Fact Sheet, UNAIDS\/WHO."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"319","DOI":"10.7326\/M14-1027","article-title":"Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: Report of 2 cases","volume":"161","author":"Henrich","year":"2014","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/487439a","article-title":"HIV: Shock and kill","volume":"487","author":"Deeks","year":"2012","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nature11286","article-title":"Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy","volume":"487","author":"Archin","year":"2012","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sogaard, O.S., Graversen, M.E., Leth, S., Olesen, R., Brinkmann, C.R., Nissen, S.K., Kjaer, A.S., Schleimann, M.H., Denton, P.W., and Hey-Cunningham, W.J. (2015). The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005142"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1016\/S2352-3018(14)70014-1","article-title":"Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: A phase 1\/2, single group, clinical trial","volume":"1","author":"Rasmussen","year":"2014","journal-title":"Lancet HIV"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"ofw189","DOI":"10.1093\/ofid\/ofw189","article-title":"Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents","volume":"3","author":"Delagreverie","year":"2016","journal-title":"Open Forum Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Thorlund, K., Horwitz, M.S., Fife, B.T., Lester, R., and Cameron, D.W. (2017). Landscape review of current HIV \u2018kick and kill\u2019 cure research\u2014Some kicking, not enough killing. BMC Infect. Dis., 17.","DOI":"10.1186\/s12879-017-2683-3"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"F7","DOI":"10.1097\/QAD.0b013e3283570620","article-title":"Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog","volume":"27","author":"Doyon","year":"2013","journal-title":"AIDS"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8118","DOI":"10.1128\/JVI.76.16.8118-8123.2002","article-title":"Effects of prostratin on T-cell activation and human immunodeficiency virus latency","volume":"76","author":"Korin","year":"2002","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Mehla, R., Bivalkar-Mehla, S., Zhang, R., Handy, I., Albrecht, H., Giri, S., Nagarkatti, P., Nagarkatti, M., and Chauhan, A. (2010). Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011160"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1097\/QAD.0000000000001064","article-title":"Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy","volume":"30","author":"Gutierrez","year":"2016","journal-title":"AIDS"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1093\/cid\/cix201","article-title":"Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with Human Immunodeficiency Virus Infection","volume":"64","author":"Vibholm","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6304","DOI":"10.1182\/blood-2008-10-186601","article-title":"IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection","volume":"113","author":"Sereti","year":"2009","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.cell.2013.09.020","article-title":"Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure","volume":"155","author":"Ho","year":"2013","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1097\/00002030-200207260-00004","article-title":"Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial)","volume":"16","author":"Stellbrink","year":"2002","journal-title":"AIDS"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.immuni.2012.01.014","article-title":"Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation","volume":"36","author":"Shan","year":"2012","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.ebiom.2016.04.019","article-title":"The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication","volume":"8","author":"Pohlmeyer","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Elliott, J.H., Wightman, F., Solomon, A., Ghneim, K., Ahlers, J., Cameron, M.J., Smith, M.Z., Spelman, T., McMahon, J., and Velayudham, P. (2014). Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004473"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Jones, R.B., O\u2019Connor, R., Mueller, S., Foley, M., Szeto, G.L., Karel, D., Lichterfeld, M., Kovacs, C., Ostrowski, M.A., and Trocha, A. (2014). Histone deacetylase inhibitors impair the elimination of HIV-infected cells by cytotoxic T-lymphocytes. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004287"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30749","DOI":"10.1038\/srep30749","article-title":"The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function","volume":"6","author":"Clutton","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1128\/jvi.63.9.3708-3713.1989","article-title":"Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: Evidence for differential gene expression","volume":"63","author":"Kim","year":"1989","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1128\/jvi.64.7.3391-3398.1990","article-title":"Structure and expression of tat-, rev-, and nef-specific transcripts of human immunodeficiency virus type 1 in infected lymphocytes and macrophages","volume":"64","author":"Popovic","year":"1990","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5011","DOI":"10.1073\/pnas.88.11.5011","article-title":"Kinetics of expression of multiply spliced RNA in early human immunodeficiency virus type 1 infection of lymphocytes and monocytes","volume":"88","author":"Klotman","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1089\/088922299309801","article-title":"Effect of long-term infection with nef-defective attenuated HIV type 1 on CD4+ and CD8+ T lymphocytes: Increased CD45RO+CD4+ T lymphocytes and limited activation of CD8+ T lymphocytes","volume":"15","author":"Zaunders","year":"1999","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1146\/annurev-virology-101416-041654","article-title":"Making Sense of Multifunctional Proteins: Human Immunodeficiency Virus Type 1 Accessory and Regulatory Proteins and Connections to Transcription","volume":"4","author":"Faust","year":"2017","journal-title":"Annu. Rev. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"508","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":"ref_31","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/0092-8674(94)90360-3","article-title":"Nef induces CD4 endocytosis: Requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain","volume":"76","author":"Aiken","year":"1994","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7117","DOI":"10.1128\/JVI.01648-08","article-title":"Nef-induced CD4 endocytosis in human immunodeficiency virus type 1 host cells: Role of p56lck kinase","volume":"83","author":"Laguette","year":"2009","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1006\/viro.1999.9642","article-title":"HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: Dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes","volume":"257","author":"Kim","year":"1999","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7413","DOI":"10.1074\/jbc.M409420200","article-title":"CD4 down-regulation by HIV-1 and simian immunodeficiency virus (SIV) Nef proteins involves both internalization and intracellular retention mechanisms","volume":"280","author":"Rose","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0960-9822(99)80283-8","article-title":"Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein","volume":"9","author":"Ross","year":"1999","journal-title":"Curr. Biol. CB"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/S0960-9822(99)80284-X","article-title":"Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner","volume":"9","author":"Lama","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"33912","DOI":"10.1074\/jbc.M303679200","article-title":"Enhanced CD4 down-modulation by late stage HIV-1 nef alleles is associated with increased Env incorporation and viral replication","volume":"278","author":"Arganaraz","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8047","DOI":"10.1128\/JVI.00252-06","article-title":"Contribution of Vpu, Env, and Nef to CD4 down-modulation and resistance of human immunodeficiency virus type 1-infected T cells to superinfection","volume":"80","author":"Wildum","year":"2006","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1128\/JVI.03230-13","article-title":"Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity","volume":"88","author":"Veillette","year":"2014","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1128\/JVI.02868-14","article-title":"The HIV-1 gp120 CD4-bound conformation is preferentially targeted by antibody-dependent cellular cytotoxicity-mediating antibodies in sera from HIV-1-infected individuals","volume":"89","author":"Veillette","year":"2015","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Prevost, J., Richard, J., Medjahed, H., Alexander, A., Jones, J., Kappes, J.C., Ochsenbauer, C., and Finzi, A. (2018). Incomplete Downregulation of CD4 Expression Affects HIV-1 Env Conformation and Antibody-Dependent Cellular Cytotoxicity Responses. J. Virol., 92.","DOI":"10.1128\/JVI.00484-18"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1128\/JVI.02973-15","article-title":"Nef Proteins from HIV-1 Elite Controllers Are Inefficient at Preventing Antibody-Dependent Cellular Cytotoxicity","volume":"90","author":"Alsahafi","year":"2015","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nm0396-338","article-title":"Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein","volume":"2","author":"Schwartz","year":"1996","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/S1074-7613(00)80553-1","article-title":"Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules","volume":"8","author":"Erdtmann","year":"1998","journal-title":"Immunity"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S1074-7613(00)80065-5","article-title":"The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells","volume":"10","author":"Cohen","year":"1999","journal-title":"Immunity"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1128\/JVI.73.3.1964-1973.1999","article-title":"Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking","volume":"73","author":"Mangasarian","year":"1999","journal-title":"J. Virol."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1128\/jvi.68.7.4650-4655.1994","article-title":"Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome","volume":"68","author":"Koup","year":"1994","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nm0297-205","article-title":"Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus","volume":"3","author":"Borrow","year":"1997","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nature03113","article-title":"Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA","volume":"432","author":"Kiepiela","year":"2004","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Altfeld, M., Kalife, E.T., Qi, Y., Streeck, H., Lichterfeld, M., Johnston, M.N., Burgett, N., Swartz, M.E., Yang, A., and Alter, G. (2006). HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030403"},{"key":"ref_52","doi-asserted-by":"crossref","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":"ref_53","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_54","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_55","doi-asserted-by":"crossref","first-page":"13702","DOI":"10.1074\/jbc.M117.797332","article-title":"The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles","volume":"292","author":"Trautz","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zhang, X., Zhou, T., Yang, J., Lin, Y., Shi, J., Zhang, X., Frabutt, D.A., Zeng, X., Li, S., and Venta, P.J. (2017). Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction. J. Virol., 91.","DOI":"10.1128\/JVI.00137-17"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6014","DOI":"10.1074\/jbc.M117.777714","article-title":"SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins","volume":"292","author":"Sood","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"10915","DOI":"10.1128\/JVI.01246-16","article-title":"The Antagonism of HIV-1 Nef to SERINC5 Particle Infectivity Restriction Involves the Counteraction of Virion-Associated Pools of the Restriction Factor","volume":"90","author":"Trautz","year":"2016","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1593","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":"ref_60","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.immuni.2006.02.016","article-title":"Human immunodeficiency virus type-1 infection impairs the formation of the immunological synapse","volume":"24","author":"Thoulouze","year":"2006","journal-title":"Immunity"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11528","DOI":"10.1128\/JVI.01423-09","article-title":"Inhibition of T-cell receptor-induced actin remodeling and relocalization of Lck are evolutionarily conserved activities of lentiviral Nef proteins","volume":"83","author":"Rudolph","year":"2009","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1182\/blood-2011-08-373209","article-title":"HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network-associated Lck signaling","volume":"119","author":"Pan","year":"2012","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Haller, C., Rauch, S., and Fackler, O.T. (2007). HIV-1 Nef employs two distinct mechanisms to modulate Lck subcellular localization and TCR induced actin remodeling. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0001212"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8425","DOI":"10.4049\/jimmunol.181.12.8425","article-title":"Induction of HIV transcription by Nef involves Lck activation and protein kinase C theta raft recruitment leading to activation of ERK1\/2 but not NF\u03baB","volume":"181","author":"Witte","year":"2008","journal-title":"J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"16513","DOI":"10.1074\/jbc.M910032199","article-title":"Synergistic activation of NFAT by HIV-1 nef and the Ras\/MAPK pathway","volume":"275","author":"Manninen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1084\/jem.20012039","article-title":"HIV-1 Nef interacts with inositol trisphosphate receptor to activate calcium signaling in T cells","volume":"195","author":"Manninen","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/35071111","article-title":"HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell","volume":"410","author":"Geleziunas","year":"2001","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1128\/JVI.76.6.2692-2702.2002","article-title":"Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis","volume":"76","author":"Greenway","year":"2002","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/nm1101-1217","article-title":"HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals","volume":"7","author":"Wolf","year":"2001","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nm0295-129","article-title":"Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes","volume":"1","author":"Finkel","year":"1995","journal-title":"Nat. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1084\/jem.189.9.1489","article-title":"Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain","volume":"189","author":"Xu","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1182\/blood-2005-03-0932","article-title":"HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation","volume":"106","author":"Muthumani","year":"2005","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"9378","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":"ref_74","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1097\/QAD.0000000000001268","article-title":"HIV cure strategists: Ignore the central nervous system at your patients\u2019 peril","volume":"31","author":"Spector","year":"2017","journal-title":"AIDS"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Gama, L., Abreu, C., Shirk, E.N., Queen, S.E., Beck, S.E., Metcalf Pate, K.A., Bullock, B.T., Zink, M.C., Mankowski, J.L., and Clements, J.E. (2018). SIV Latency in Macrophages in the CNS. Curr. Top. Microbiol. Immunol.","DOI":"10.1007\/82_2018_89"},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.1128\/JVI.02185-07","article-title":"Human immunodeficiency virus type 1 Nef recruits the guanine exchange factor Vav1 via an unexpected interface into plasma membrane microdomains for association with p21-activated kinase 2 activity","volume":"82","author":"Rauch","year":"2008","journal-title":"J. Virol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.chom.2009.06.004","article-title":"HIV-1 Nef interferes with host cell motility by deregulation of Cofilin","volume":"6","author":"Stolp","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.1128\/JVI.02467-09","article-title":"Lentiviral Nef proteins utilize PAK2-mediated deregulation of cofilin as a general strategy to interfere with actin remodeling","volume":"84","author":"Stolp","year":"2010","journal-title":"J. Virol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/nri2041","article-title":"Modulation of the immunological synapse: A key to HIV-1 pathogenesis?","volume":"7","author":"Fackler","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5289","DOI":"10.4049\/jimmunol.155.11.5289","article-title":"Extracellular Nef protein regulates productive HIV-1 infection from latency","volume":"155","author":"Fujinaga","year":"1995","journal-title":"J. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1089\/088922202753614227","article-title":"Extracellular Nef protein activates signal transduction pathway from Ras to mitogen-activated protein kinase cascades that leads to activation of human immunodeficiency virus from latency","volume":"18","author":"Tobiume","year":"2002","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1074\/jbc.M209622200","article-title":"Exogenous Nef protein activates NF-\u03baB, AP-1, and c-Jun N-terminal kinase and stimulates HIV transcription in promonocytic cells. Role in AIDS pathogenesis","volume":"278","author":"Varin","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"24090","DOI":"10.1038\/srep24090","article-title":"Tuning of AKT-pathway by Nef and its blockade by protease inhibitors results in limited recovery in latently HIV infected T-cell line","volume":"6","author":"Kumar","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0014-5793(96)00859-9","article-title":"Soluble Nef antigen of HIV-1 is cytotoxic for human CD4+ T cells","volume":"393","author":"Fujii","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1182\/blood.V98.9.2752","article-title":"HIV-1 Nef activates STAT1 in human monocytes\/macrophages through the release of soluble factors","volume":"98","author":"Federico","year":"2001","journal-title":"Blood"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/j.1600-0854.2009.01006.x","article-title":"HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells","volume":"11","author":"Lenassi","year":"2010","journal-title":"Traffic"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"167","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":"ref_89","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s12977-015-0216-y","article-title":"Latent HIV-1 is activated by exosomes from cells infected with either replication-competent or defective HIV-1","volume":"12","author":"Arenaccio","year":"2015","journal-title":"Retrovirology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0014-5793(97)01255-6","article-title":"Nef protein of HIV-1 induces apoptotic cytolysis of murine lymphoid cells independently of CD95 (Fas) and its suppression by serine\/threonine protein kinase inhibitors","volume":"417","author":"Okada","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1099\/0022-1317-81-12-2905","article-title":"T-tropic human immunodeficiency virus (HIV) type 1 Nef protein enters human monocyte-macrophages and induces resistance to HIV replication: A possible mechanism of HIV T-tropic emergence in AIDS","volume":"81","author":"Alessandrini","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3109\/10409231003628015","article-title":"ADAM-17: The enzyme that does it all","volume":"45","author":"Gooz","year":"2010","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.molcel.2012.12.004","article-title":"HIV Nef, paxillin, and Pak1\/2 regulate activation and secretion of TACE\/ADAM10 proteases","volume":"49","author":"Lee","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1126\/science.1071924","article-title":"TNF-R1 signaling: A beautiful pathway","volume":"296","author":"Chen","year":"2002","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.chom.2009.06.009","article-title":"Massive secretion by T cells is caused by HIV Nef in infected cells and by Nef transfer to bystander cells","volume":"6","author":"Muratori","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1172\/JCI97555","article-title":"Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells","volume":"128","author":"Huang","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Mujib, S., Saiyed, A., Fadel, S., Bozorgzad, A., Aidarus, N., Yue, F.Y., Benko, E., Kovacs, C., Emert-Sedlak, L.A., and Smithgall, T.E. (2017). Pharmacologic HIV-1 Nef blockade promotes CD8 T cell-mediated elimination of latently HIV-1-infected cells in vitro. JCI Insight, 2.","DOI":"10.1172\/jci.insight.93684"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1007\/s00018-014-1656-6","article-title":"Histone deacetylase inhibitors and cell death","volume":"71","author":"Zhang","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1126\/science.281.5384.1860","article-title":"Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx","volume":"281","author":"Chang","year":"1998","journal-title":"Science"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/S1097-2765(00)80283-X","article-title":"ASK1 is essential for JNK\/SAPK activation by TRAF2","volume":"2","author":"Nishitoh","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1093\/emboj\/17.9.2596","article-title":"Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1","volume":"17","author":"Saitoh","year":"1998","journal-title":"EMBO J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1126\/science.275.5296.90","article-title":"Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK\/JNK and p38 signaling pathways","volume":"275","author":"Ichijo","year":"1997","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6635","DOI":"10.1038\/sj.onc.1203076","article-title":"Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway","volume":"18","author":"Fang","year":"1999","journal-title":"Oncogene"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/417095a","article-title":"HIV preferentially infects HIV-specific CD4+ T cells","volume":"417","author":"Douek","year":"2002","journal-title":"Nature"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/12\/677\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:33:27Z","timestamp":1760196807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/12\/677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,30]]},"references-count":104,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["v10120677"],"URL":"https:\/\/doi.org\/10.3390\/v10120677","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2018,11,30]]}}}