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Massive Secretion by T Cells Is Caused by HIV Nef in Infected Cells and by Nef Transfer to Bystander Cells
Open accessAbstract
The HIV Nef protein mediates endocytosis of surface receptors that correlates with disease progression, but the link between this Nef function and HIV pathogenesis is not clear. Here, we report that Nef-mediated activation of membrane trafficking is bidirectional, connecting endocytosis with exocytosis as occurs in activated T cells. Nef expression induced an extensive secretory activity in infected and, surprisingly, also in noninfected T cells, leading to the massive release of microvesicle clusters, a phenotype observed in vitro and in 36%-87% of primary CD4 T cells from HIV-infected individuals. Consistent with exocytosis in noninfected cells, Nef is transferred to bystander cells upon cell-to-cell contact and subsequently induces secretion in an Erk1/2-dependent manner. Thus, HIV Nef alters membrane dynamics, mimicking those of activated T cells and causing a transfer of infected cell signaling (TOS) to bystander cells. This mechanism may help explain the detrimental effect on bystander cells seen in HIV infection.
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“One common feature in these studies is that the MVBs involved may not be classical late-endosomes.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [64]
In the citing paper
“Indeed, clustered ILVs have been observed in other cell types in mammals and nematodes in the absence of DCGs and in specific pathological scenarios36,64.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [64]
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Exosomes Derived from HIV-1-infected Cells Contain Trans-activation Response Element RNA
Narayanan, A., Iordanskiy, S., Das, R., Van Duyne, R., Santos, S., Jaworski, E., Guendel, I., Sampey, G., Dalby, E., Iglesias-Ussel, M., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.438895 · Cited by 316
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Madison, M. N., & Okeoma, C. M. (2015) · Viruses · doi:10.3390/v7072810 · Cited by 175
“There is evidence that HIV-1 infection or transduction of cells with the HIV-1 accessory protein, Nef, increases the cellular release of exosomes [34,76–78].”
BackgroundArenaccio, C., Chiozzini, C., Cabezas, S. C., Manfredi, F., Affabris, E., Baur, A. S., & Federico, M. (2014) · Journal of Virology · doi:10.1128/jvi.01712-14 · Cited by 170
“Exosomes from HIV1-infected cells incorporate Gag (5) and Nef HIV-1 proteins (6, 7).”
BackgroundSelf-citationExtracellular vesicles as modulators of wound healing
Cabral, J., Ryan, A. E., Griffin, M. D., & Ritter, T. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.01.018 · Cited by 171
Raymond, A., Campbell, T., Khan, M. B., Lang, M. J., Huang, M. B., Bond, V. C., & Powell, M. D. (2010) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2009.0170 · Cited by 172
“In fact, a recent study indicates that HIV-1infected T cells undergo a Nef-dependent massive increase in exocytosis of microvesicles containing Nef and/or FasL.(62) This report supports our study and suggests that Nef microvesicles may play a factor in HIV-induced T cell apoptosis.”
ResultBiogenesis and Functions of Exosomes and Extracellular Vesicles
Dreyer, F. S., & Baur, A. S. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3753-0_15 · Cited by 139
Self-citationMukhamedova, N., Hoang, A., Dragoljevic, D., Dubrovsky, L., Pushkarsky, T., Low, H., Ditiatkovski, M., Fu, Y., Ohkawa, R., Meikle, P. J., et al. (2019) · PLoS Pathogens · doi:10.1371/journal.ppat.1007907 · Cited by 133
“Interestingly, Nef itself is a potent activator of microvesicle exocytosis, and mechanism of release of Nef-containing exosomes from infected cells has been recently described [9, 51].”
BackgroundExtracellular Vesicles and Their Convergence with Viral Pathways
Wurdinger, T. D., Gatson, N. T., Balaj, L., Kaur, B., Breakefield, X. O., & Pegtel, D. M. (2012) · Advances in Virology · doi:10.1155/2012/767694 · Cited by 130
“HIV Nef-induced microvesicle release from infected and noninfected cells [39, 40] can induce apoptosis in CD4+ T cells [41] and convey resistance to HIV infection [61].”
BackgroundHIV ‐1 Nef: Taking Control of Protein Trafficking
Pereira, E. A., & daSilva, L. L. P. (2016) · Traffic · doi:10.1111/tra.12412 · Cited by 141
“There are Traffic 2016; 17: 976–996 987 a variety of types of EVs that differ in size, constitution and the cell site from where they originate.”
BackgroundInfluentialRaymond, A., Diaz, P., Chevelon, S., Agudelo, M., Yndart, A., Ding, H., Kaushik, A. K., Jayant, R. D., Nikkhah-Moshaie, R., Roy, U. B., et al. (2015) · Journal of NeuroVirology · doi:10.1007/s13365-015-0397-0 · Cited by 118
Nef Neutralizes the Ability of Exosomes from CD4+ T Cells to Act as Decoys during HIV-1 Infection
de Carvalho, J. V., de Castro, R. O., da Silva, E. Z. M., Silveira, P. P., da Silva-Januário, M. E., Arruda, E., Jamur, M. C., Oliver, C., Aguiar, R. S., & daSilva, L. L. P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113691 · Cited by 117
“In addition to being secreted in exosomes, HIV-1 Nef was previously shown to induce the release of these extracellular vesicles [39, 40].”
BackgroundMethodInfluentialLee, J., Schierer, S., Blume, K., Dindorf, J., Wittki, S., Xiang, W., Ostalecki, C., Koliha, N., Wild, S., Schuler, G., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.03.004 · Cited by 107
“EV purification was performed essentially as described previously (Muratori et al., 2009; Thery et al., 2009).”
BackgroundMethodResultInfluentialSelf-citationJC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
Morris‐Love, J., Gee, G. V., O’Hara, B. A., et al. (2019) · mBio · doi:10.1128/mbio.00379-19 · Cited by 107
Logozzi, M., Raimo, R. D., Mizzoni, D., & Fais, S. (2020) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2020.06.011 · Cited by 109
Self-citationFerdin, J., Goričar, K., Dolžan, V., Plemenitaš, A., Martin, J. N., Peterlin, B. M., Deeks, S. G., & Lenassi, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0191613 · Cited by 103
“Third, Nef was shown to facilitate its own export with exosomes from Nef-expressing or HIVinfected T-cells in vitro [14, 16, 17], although Luo et al.”
BackgroundBiogenesis and Function of T Cell-Derived Exosomes
Ventimiglia, L. N., & Alonso, M. A. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00084 · Cited by 103
“Since cholesterol is highly enriched in ILV of MVE but poorly represented in lysosomes, a role for cholesterol was proposed in the intraluminal sorting of membranes destined for secretion as exosomes (Möbius et al., 2003).”
BackgroundDar, G. H., Mendes, C. C., Kuan, W.-L., Speciale, A. A., Conceição, M., Görgens, A., Uliyakina, I., Lobo, M. J., Lim, W. F., EL Andaloussi, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27056-3 · Cited by 100
HIV-1 Nef Inhibits Ruffles, Induces Filopodia, and Modulates Migration of Infected Lymphocytes
Nobile, C., Rudnicka, D., Hasan, M., Aulner, N., Porrot, F., Machu, C., Renaud, O., Prévost, M., Hivroz, C., Schwartz, O., et al. (2009) · Journal of Virology · doi:10.1128/jvi.02230-09 · Cited by 104
“Interestingly, Nef transfer between T cells may also occur through exchange of microvesicles or patches of plasma membrane (33).”
BackgroundTiede, L. M., Cook, E. A., Morsey, B., & Fox, H. S. (2011) · Cell Death and Disease · doi:10.1038/cddis.2011.128 · Cited by 99
HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases
Lee, J., Wittki, S., Bräu, T., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.004 · Cited by 96
“We and others have previously demonstrated that HIV Nef induces the secretion of extracellular vesicles (EVs) in vitro and in vivo (Muratori et al., 2009; Lenassi et al., 2010; Raymond et al., 2011).”
BackgroundMethodInfluentialSelf-citationArenaccio, C., Anticoli, S., Manfredi, F., Chiozzini, C., Olivetta, E., & Federico, M. (2015) · Retrovirology · doi:10.1186/s12977-015-0216-y · Cited by 94
“The convergence of exosome and HIV biogenesis implies the possibility that viral products can be uploaded in exosomes as observed in the case of HIV-1 Gag [9] and Nef [10, 11].”
BackgroundSelf-citationMukerji, J., Olivieri, K. C., Misra, V., Agopian, K. A., & Gabuzda, D. H. (2012) · Retrovirology · doi:10.1186/1742-4690-9-33 · Cited by 97
“Exosomes or microvesicles that contain Nef [24] or proinflammatory molecules such as cytokines [86] contribute to cell activation [25] and activation-induced apoptosis [24].”
BackgroundResultInfluentialHIV-1 Nef: a multifaceted modulator of T cell receptor signaling
Abraham, L., & Fackler, O. (2012) · Cell Communication and Signaling · doi:10.1186/1478-811x-10-39 · Cited by 99
“Nef has been reported to trigger the release of exosome microvesicles that are massively secreted to bystander cells upon T-cell activation [115,116].”
BackgroundAssociation of Cytokines With Exosomes in the Plasma of HIV-1–Seropositive Individuals
Konadu, K. A., Chu, J., Huang, M. B., et al. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiu676 · Cited by 89
The HIV Nef protein modulates cellular and exosomal miRNA profiles in human monocytic cells
Aqil, M., Naqvi, A. R., Mallik, S., Bandyopadhyay, S., Maulik, U., & Jameel, S. (2014) · Journal of Extracellular Vesicles · doi:10.3402/jev.v3.23129 · Cited by 89
“exosome biogenesis, the secretion of these vesicles (27),”
BackgroundAntiretroviral Drugs Alter the Content of Extracellular Vesicles from HIV-1-Infected Cells
DeMarino, C., Pleet, M. L., Cowen, M., Barclay, R. A., Akpamagbo, Y., Erickson, J. W., Ndembi, N., Charurat, M., Jumare, J., Bwala, S. A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-25943-2 · Cited by 86
Modern Techniques for the Isolation of Extracellular Vesicles and Viruses
McNamara, R. P., & Dittmer, D. P. (2019) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09874-x · Cited by 84
O’Hara, B. A., Morris‐Love, J., Gee, G. V., Haley, S. A., & Atwood, W. J. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008371 · Cited by 79
Lattanzi, L., & Federico, M. (2012) · Vaccine · doi:10.1016/j.vaccine.2012.10.010 · Cited by 81
“membrane lipid raft microdomains [14–20].”
BackgroundSelf-citationHIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo
Stolp, B., Imle, A., Coelho, F. M., Hons, M., Gorina, R., Lyck, R., Stein, J. V., & Fackler, O. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1204322109 · Cited by 79
Transfer of Intracellular HIV Nef to Endothelium Causes Endothelial Dysfunction
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Multifunctional role of exosomes in viral diseases: From transmission to diagnosis and therapy
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Extracellular vesicles and chronic inflammation during HIV infection
Pérez, P. S., Romaniuk, M. A., Duette, G., Zhao, Z., Huang, Y., Jaular, L. M., Witwer, K. W., Théry, C., & Ostrowski, M. (2019) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2019.1687275 · Cited by 73
“human and simian immunodeficiency virus has been reported to be incorporated into EVs [89,105,113].”
BackgroundJaular, L. M., Névo, N., Schessner, J. P., Tkach, M., Jouve, M. J., Dingli, F., Loew, D., Witwer, K. W., Ostrowski, M., Borner, G. H. H., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020105492 · Cited by 71
“Nef had been observed in clusters of microvesicles (Muratori et al, 2009) or recovered exclusively in CD45 + EVs (Raymond et al, 2011), or in both virus-and non-virus-containing fractions of a velocity gradient (Lenassi et al, 2010).”
Shelton, M. N., Huang, M., Ali, S. A., Powell, M. D., & Bond, V. C. (2011) · Journal of Virology · doi:10.1128/jvi.05720-11 · Cited by 69
“More recently, our group and others have found that secreted Nef protein is predominantly found in exosomes (exNef), small membrane-bound vesicles in both the plasma of HIV-1-infected patients and in the culture medium of Jurkat T cells infected with HIV-1 or transfected with HIV-1 nef (2, 12, 63, 72, 83).”
BackgroundResultInfluentialFifty Years of JC Polyomavirus: A Brief Overview and Remaining Questions
Atkinson, A. L., & Atwood, W. J. (2020) · Viruses · doi:10.3390/v12090969 · Cited by 68
The Multifaceted Functions of Exosomes in Health and Disease: An Overview
Arenaccio, C., & Federico, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-4397-0_1 · Cited by 66
Self-citationExosomes in HIV infection: A review and critical look
Ellwanger, J. H., Veit, T. D., & Chies, J. A. B. (2017) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2017.05.021 · Cited by 70
Monitoring multiple myeloma by idiotype-specific peptide binders of tumor-derived exosomes
Iaccino, E., Mimmi, S., Dattilo, V., et al. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0730-8 · Cited by 66
Extracellular vesicles during Herpes Simplex Virus type 1 infection: an inquire
Kalamvoki, M., & Deschamps, T. (2016) · Virology Journal · doi:10.1186/s12985-016-0518-2 · Cited by 68
“Nef also increases the exosome production in HIV-1 infected or Nef-transduced cells [56].”
Arenaccio, C., Chiozzini, C., Cabezas, S. C., Manfredi, F., & Federico, M. (2014) · Retrovirology · doi:10.1186/1742-4690-11-46 · Cited by 64
“In addition, western blot analysis revealed that, consistently with what previously described for exosomes from Gag- [20] or Nef-expressing cells [21,22], both HIV-1 CAp24 and Nef proteins associate with exosomes from F12/Hut-78 cells (Figure 2C).”
BackgroundSelf-citationThe HIV-1 Nef Protein Binds Argonaute-2 and Functions as a Viral Suppressor of RNA Interference
Aqil, M., Naqvi, A. R., Bano, A. S., & Jameel, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074472 · Cited by 67
“This was observed earlier for T cells as well [25,41].”
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“Nef might also access CD8 T cells through cell-cell contacts, as was described to occur between infected and bystander T cells (61).”
BackgroundSequences within RNA coding for HIV-1 Gag p17 are efficiently targeted to exosomes
Cabezas, S. C., & Federico, M. (2012) · Cellular Microbiology · doi:10.1111/cmi.12046 · Cited by 62
“This was already proven for both Gag (Fang et al., 2007) and Nef HIV-1 proteins (Muratori et al., 2009; Lenassi et al., 2010).”
BackgroundSelf-citationBaur, A. S., Lutz, M. B., Schierer, S., Beltrame, L., Theiner, G., Zinser, E., Ostalecki, C., Heidkamp, G. F., Haendle, I., Erdmann, M., et al. (2013) · Blood · doi:10.1182/blood-2012-09-456988 · Cited by 64
Self-citationPan, X., Rudolph, J. M., Abraham, L., et al. (2011) · Blood · doi:10.1182/blood-2011-08-373209 · Cited by 63
Trautz, B., Pierini, V., Wombacher, R., et al. (2016) · Journal of Virology · doi:10.1128/jvi.01246-16 · Cited by 62
“Similar results were obtained upon coexpression of Nef, which has been reported to increase the release of extracellular vesicles (42).”
BackgroundResultTransmission of HBV DNA Mediated by Ceramide-Triggered Extracellular Vesicles
Sanada, T., Hirata, Y., Naito, Y., Yamamoto, N., Kikkawa, Y., Ishida, Y., Yamasaki, C., Tateno, C., Ochiya, T., & Kohara, M. (2016) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.10.003 · Cited by 63
Extracellular vesicles from organoids and 3D culture systems
Abdollahi, S. (2020) · Biotechnology and Bioengineering · doi:10.1002/bit.27606 · Cited by 65
“EVs also modulate the immune response and can carry mutated genetic material in pathologies such as HIV, cancer, and other disease states (Dreyer & Baur, 2016; Muratori et al., 2009; Robbins & Morelli, 2014; Zha et al., 2017).”
BackgroundHu, G., Yang, L., Cai, Y. C., Niu, F., Mezzacappa, F., Callen, S. E., Fox, H. S., & Buch, S. J. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.336 · Cited by 59
Human immunodeficiency virus (HIV) type-1, HIV-2 and simian immunodeficiency virus Nef proteins
Laguette, N., Brégnard, C., Bénichou, S., & Basmaciogullari, S. (2010) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2010.05.003 · Cited by 72
Nef is secreted in exosomes from Nef.GFP-expressing and HIV-1-infected human astrocytes
Dominkuš, P. P., Ferdin, J., Plemenitaš, A., et al. (2017) · Journal of NeuroVirology · doi:10.1007/s13365-017-0552-x · Cited by 58
“CIITA cells (Stumptner-Cuvelette et al. 2003), and induces extracellular vesicle (EV) secretion from various cells (Lenassi et al. 2010; Muratori et al. 2009).”
BackgroundResultInfluentialThe Role of Extracellular Vesicles as Allies of HIV, HCV and SARS Viruses
Giannessi, F., Aiello, A., Franchi, F., Percario, Z. A., & Affabris, E. (2020) · Viruses · doi:10.3390/v12050571 · Cited by 60
“Different studies have shown how Nef increases vesicular production [94,95] and its association with EVs, which was observed both in in vitro and in vivo studies [94–96].”
BackgroundThe Ambiguous Roles of Extracellular Vesicles in HIV Replication and Pathogenesis
Dias, M. V. S., Costa, C. S., & daSilva, L. L. P. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.02411 · Cited by 59
“On the other hand, the non-structural Nef protein, a major determinant of HIV-1 pathogenicity that manipulates protein trafficking in host cells (reviewed by Pereira and daSilva, 2016), is the most well-known HIV-1 factor released within EVs (Campbell et al., 2008; Muratori et al., 2009; Lenassi et al., 2010; De Carva…”
BackgroundEn bloc release of MVB‐like small extracellular vesicle clusters by colorectal carcinoma cells
Valcz, G., Buzás, E. I., Kittel, Á., Krenács, T., Visnovitz, T., Spisák, S., Török, G., Homolya, L., Zsigrai, S., Kiszler, G., et al. (2019) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2019.1596668 · Cited by 52
“[7], multivesicular spheres [8] and released multivesicular cargo [9].”
BackgroundIsolation of Exosomes from the Plasma of HIV-1 Positive Individuals
Konadu, K. A., Huang, M. B., Roth, W. W., Armstrong, W. S., Powell, M. D., Villinger, F. J., & Bond, V. C. (2016) · Journal of Visualized Experiments · doi:10.3791/53495 · Cited by 52
Boullé, M., Müller, T. G., Dähling, S., Ganga, Y., Jackson, L., Mahamed, D., Lance, O., Lustig, G., Neher, R. A., & Sigal, A. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005964 · Cited by 52
“Other HIV proteins, such as Nef, may also modify the physiology of yet uninfected cells upon cell-to-cell contact [45].”
Characterization of Dendritic Cell-Derived Extracellular Vesicles During Dengue Virus Infection
Martins, S. D. T., Kuczera, D., Lötvall, J. O., Bordignon, J., & Alves, L. R. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.01792 · Cited by 49
“Dendritic cell-derived EVs can be important during viral infections, as is shown for HIV, where dendritic cell-derived EVs can carry HIV particles, leading to trans-infection of CD4 T cells and helping in the dissemination of HIV (Muratori et al., 2009; Izquierdo-Useros et al., 2010).”
BackgroundThe role of exosomal transport of viral agents in persistent HIV pathogenesis
Patters, B. J., & Kumar, S. (2018) · Retrovirology · doi:10.1186/s12977-018-0462-x · Cited by 49
Mangino, G., Percario, Z. A., Fiorucci, G., Vaccari, G., Acconcia, F., Chiarabelli, C., Leone, S., Noto, A., Horenkamp, F. A., Manrique, S., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022982 · Cited by 46
Quantitative proteomic analysis of exosomes from HIV-1 infected lymphocytic cells
Li, M., Aliotta, J., Asara, J. M., Tucker, L., Quesenberry, P., Lally, M., & Ramratnam, B. (2012) · Proteomics · doi:10.1002/pmic.201100376 · Cited by 49
MicroRNA-Mediated Restriction of HIV-1 in Resting CD4+ T Cells and Monocytes
Chiang, K., & Rice, A. P. (2012) · Viruses · doi:10.3390/v4091390 · Cited by 47
“As Nef appears to dramatically increase microvesicle secretion [125], it is therefore probable that HIV-1 infection may cause changes in expression of secreted miRNAs which may eventually affect cells distributed throughout the periphery.”
BackgroundKumar, A., Abbas, W., Colin, L., Khan, K. A., Bouchat, S., Varin, A., Larbi, A., Gatot, J., Kabeya, K., Vanhulle, C., et al. (2016) · Scientific Reports · doi:10.1038/srep24090 · Cited by 44
Ferrantelli, F., Manfredi, F., Chiozzini, C., Anticoli, S., Olivetta, E., Arenaccio, C., & Federico, M. (2018) · Molecular Biotechnology · doi:10.1007/s12033-018-0114-3 · Cited by 43
Self-citationCutting Edge: Regulation of Exosome Secretion by the Integral MAL Protein in T Cells
Ventimiglia, L. N., Fernández‐Martín, L., Martínez‐Alonso, E., Antón, O. M., Guerra, M., Martínez‐Menárguez, J. A., Andrés, G., & Alonso, M. A. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500891 · Cited by 43
“Expression of the HIV-1 accessory protein Nef in T cells induces massive secretion of exosome markers (16, 17).”
BackgroundOstalecki, C., Wittki, S., Lee, J., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.10.027 · Cited by 41
“Hence, this secretion type, which we detailed with electronmicrographs in our previous work (Muratori et al., 2009), is different frommicrovesicle (Cocucci et al.”
BackgroundMethodResultInfluentialSelf-citationNef-induced CCL2 Expression Contributes to HIV/SIV Brain Invasion and Neuronal Dysfunction
Lehmann, M. H., Lehmann, J. M., & Erfle, V. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02447 · Cited by 42
“It was later confirmed that Nef is released from HIV-infected cells (70, 71) by microvesicles and it was even claimed that this occurs via exosomes (72).”
BackgroundAqil, M., Mallik, S., Bandyopadhyay, S., Maulik, U., & Jameel, S. (2015) · BioMed Research International · doi:10.1155/2015/492395 · Cited by 39
“Later, it was found in exosomes from Nef-GFP transfectedHEK293 cells, transfected human T cell lines including Jurkat and SupT1 cells, and HIV infected primary as well as transformed cells [5, 12, 13].”
BackgroundUsami, Y., Popov, S., & Göttlinger, H. (2014) · Journal of Virology · doi:10.1128/jvi.01933-13 · Cited by 46
Kumawat, K., Pathak, S. K., Spetz, A., Kundu, M., & Basu, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.073320 · Cited by 39
Exosomes Are Unlikely Involved in Intercellular Nef Transfer
Luo, X., Fan, Y., Park, I.-W., & He, J. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124436 · Cited by 35
“Consistent with previous findings [41, 42], co-culture between Nef.”
BackgroundResultImle, A., Abraham, L., Tsopoulidis, N., Hoflack, B., Saksela, K., & Fackler, O. (2015) · mBio · doi:10.1128/mbio.01309-15 · Cited by 34
TIM-mediated inhibition of HIV-1 release is antagonized by Nef but potentiated by SERINC proteins
Li, M., Waheed, A. A., Yu, J., Zeng, C., Chen, H.-Y., Zheng, Y.-M., Feizpour, A., Reinhard, B. M., Gummuluru, S., Lin, S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819475116 · Cited by 32
“interference by Nef of the TIM–PS interaction is topologically unfavorable, because Nef is essentially an intracellular protein despite the fact that it can be secreted into culture media and has been detected in exosomes (52, 53).”
BackgroundNon-productive HIV-1 infection of human glomerular and urinary podocytes
Khatua, A. K., Taylor, H. E., Hildreth, J. E. K., et al. (2010) · Virology · doi:10.1016/j.virol.2010.09.005 · Cited by 30
“Indeed, accumulation of functional Nef in exosomes released from infected T cells has been documented (Ali et al., 2010; Lenassi et al., 2010; Muratori et al., 2009).”
BackgroundIncorporation of Heterologous Proteins in Engineered Exosomes
Manfredi, F., Bonito, P. D., Arenaccio, C., et al. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3753-0_18 · Cited by 30
Self-citationExtracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC
Schierer, S., Ostalecki, C., Zinser, E., Lamprecht, R., Plosnita, B., Stich, L., Dörrie, J., Lutz, M. B., Schuler, G., & Baur, A. S. (2018) · Life Science Alliance · doi:10.26508/lsa.201800093 · Cited by 30
“EV puri fi cation was performed essentially as described previously (Muratori et al, 2009; Thery et al, 2009).”
Self-citationLee, J., Ostalecki, C., Oberstein, T. J., Schierer, S., Zinser, E., Eberhardt, M., Blume, K., Plosnita, B., Stich, L., Bruns, H., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103903 · Cited by 32
Self-citationGelais, C. S., Coleman, C. M., Wang, J., & Wu, L. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034521 · Cited by 29
“cells to bystander cells upon cell-to-cell contact and contribute to the detrimental effect on bystander cells in viral infection”
BackgroundHodge, A. L., Baxter, A. A., & Poon, I. K. H. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.3ru1220-801r · Cited by 27
Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome
Geskin, L. J., Akilov, O. E., Kwon, S., Schowalter, M. K., Watkins, S. C., Whiteside, T. L., Butterfield, L. H., & Falo, L. D. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-2090-z · Cited by 26
“Since only activated T cells develop late endosomes [42] that are required for pH unfolding of the toxin, it was proposed that resting T cells survive DD treatment [41].”
Ferrantelli, F., Chiozzini, C., Manfredi, F., Giovannelli, A., Leone, P., & Federico, M. (2021) · Vaccines · doi:10.3390/vaccines9030240 · Cited by 24
“We previously described the ability of Human Immunodeficiency Virus (HIV) -1 Nef to incorporate into EVs released by multiple cell types, including CD4+ T lymphocytes and dendritic cells [30].”
MethodSelf-citationThe promise of exosome applications in treating central nervous system diseases
Mattingly, J., Li, Y., Bihl, J. C., & Wang, J. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13743 · Cited by 23
da Silva-Januário, M. E., da Costa, C. S., Tavares, L., Oliveira, A. K., Januário, Y. C., de Carvalho, A. N., Cassiano, M. H. A., Rodrigues, R. L., Miller, M. E., Palameta, S., et al. (2023) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2023.100676 · Cited by 25
HIV-Nef and AIDS pathogenesis: are we barking up the wrong tree?
Baur, A. S. (2011) · Trends in Microbiology · doi:10.1016/j.tim.2011.06.002 · Cited by 24
Self-citationInnate extracellular vesicles from melanoma patients suppress β-catenin in tumor cells by miRNA-34a
Lee, J., Dindorf, J., Eberhardt, M., Lai, X., Ostalecki, C., Koliha, N., Gross, S., Blume, K., Bruns, H., Wild, S., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201800205 · Cited by 23
“We described an additional type of EV, budding directly from endosomal compartments (Muratori et al, 2009; Ostalecki et al, 2016), characteristically containing numerous cytokines, chemokines, and soluble factors (hereafter termed CCF), ADAM10/17 proteases, and a surface marker set that is…”
BackgroundSelf-citationShedding Light on the Role of Extracellular Vesicles in HIV Infection and Wound Healing
Alqatawni, A., Sharma, A. L., Attilus, B., Tyagi, M., & Daniel, R. (2020) · Viruses · doi:10.3390/v12060584 · Cited by 26
Extracellular vesicles in COVID-19 prognosis, treatment, and vaccination: an update
Hernández-Díazcouder, A., Díaz-Godínez, C., & Carrero, J. C. (2023) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-023-12468-6 · Cited by 23
Perrin, S., Cremer, J., Roll, P., Zaegel‐Faucher, O., Menard, A., Reynes, J., Dellamonica, P., Naqvi, A., Micallef, J., Jouve, É., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041129 · Cited by 22
“Both direct and bystander effects are associated with HIV-1 infection [51] clearly impacted lymphocyte mitochondria while monocyte mitochondria appeared to be less sentitive.”
Characterization of Nef expression in different brain regions of SIV-infected macaques
Yarandi, S. S., Robinson, J. A., Vakili, S., Donadoni, M., Burdo, T. H., & Sariyer, I. K. (2020) · PLoS ONE · doi:10.1371/journal.pone.0241667 · Cited by 23
The Role of Viral Proteins in the Regulation of Exosomes Biogenesis
Jia, X., Yin, Y., Chen, Y., & Mao, L. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.671625 · Cited by 22
Finetti, F., Cassioli, C., & Baldari, C. T. (2017) · F1000Research · doi:10.12688/f1000research.11944.1 · Cited by 22
Ananth, S., Morath, K., Trautz, B., Tibroni, N., Shytaj, I. L., Obermaier, B., Stolp, B., Lušić, M., & Fackler, O. (2019) · Journal of Virology · doi:10.1128/jvi.01398-19 · Cited by 20
“While our study suggests that Nef-phosphorylating NAKC activity is dispensable for the recruitment of Nef into EVs, future studies will need to address the specific molecular determinants by which HIV-1 Nef modulates the content of EVs in HIV patients (48, 68, 69).”
BackgroundMitochondrial dysfunctions in HIV infection and antiviral drug treatment
Ganta, K. K., & Chaubey, B. (2019) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2019.1692814 · Cited by 20
Complexities of JC Polyomavirus Receptor-Dependent and -Independent Mechanisms of Infection
Morris‐Love, J., & Atwood, W. J. (2022) · Viruses · doi:10.3390/v14061130 · Cited by 21
Fackler, O. (2015) · Viruses · doi:10.3390/v7122970 · Cited by 20
“In addition, Nef also impairs host cell actin dynamics and motility, drives the release of extracellular vesicles, and has been implicated in the regulation of cell survival [2,19–27].”
BackgroundThe Contribution of Extracellular Nef to HIV-Induced Pathogenesis
Olivetta, E., Arenaccio, C., Manfredi, F., Anticoli, S., & Federico, M. (2015) · Current Drug Targets · doi:10.2174/1389450116666151001110126 · Cited by 20
Self-citationKammula, E. C., Mötter, J., Gorgels, A., Jonas, E., Hoffmann, S., & Willbold, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051578 · Cited by 19
“Also in recent literature, Nef has been reported to be translocated from HIV-1 infected cells to bystander cells via secretion, trogocytosis or nanotubes [37] [38] [39] and it is conceivable that Nef might be also secreted in the CNS from microglial cells and astrocytes and thereby might indirectly affect neurons or o…”
Background
Metadata
- Authors
- Muratori, C., Cavallin, L. E., Krätzel, K., Tinari, A., De Milito, A., Fais, S., D'Aloja, P., Federico, M., Vullo, V., Fomina, A., Mesri, E. A., Superti, F., & Baur, A. S.
- Affiliations
- University of Miami (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Istituto Superiore di Sanità (IT)
- Sapienza University of Rome (IT)
- University of California, Davis (US)
- Corresponding author
- Baur, Andreas S.
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 6
- Issue
- 3
- Pages
- 218-230
- ISSN
- 1931-3128 (ISSN-L)
- OpenAlex
- W1983073673
- Semantic Scholar
- 4882f11c55140c561fa862059b7d2ec9e08c0fa5
- Cited by
- 164
- References
- 82
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 17 · 2017: 12 · 2016: 15 · 2015: 13 · 2014: 11 · 2013: 8 · 2012: 19
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1415 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Cancer Institute (CA 75918, R01CA075918)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Keywords
- HIV Nef, exocytosis, endocytosis, microvesicles, bystander cells, cell-to-cell transmission, ERK signaling, membrane trafficking, CD4+ T cells, HIV pathogenesis
- MeSH terms
- Cells, Cultured, Endocytosis, Exocytosis, Humans, Lymphocyte Activation, T-Lymphocytes, HIV-1, HIV Infections, Protein Transport, Secretory Vesicles, Bystander Effect, nef Gene Products, Human Immunodeficiency Virus, Host-Pathogen Interactions, Secretory Pathway
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