Massive Secretion by T Cells Is Caused by HIV Nef in Infected Cells and by Nef Transfer to Bystander Cells

Muratori, Claudia; Cavallin, Lucas E.; Krätzel, Kirsten; Tinari, Antonella; De Milito, Angelo; Fais, Stefano; D'Aloja, Paola; Federico, Maurizio; Vullo, Vincenzo; Fomina, Alla; Mesri, Enrique A.; Superti, Fabiana; Baur, Andreas S.

doi:10.1016/j.chom.2009.06.009

Cited by 164HIV Research and TreatmentCellular transport and secretionT-cell and Retrovirus Studies

Massive Secretion by T Cells Is Caused by HIV Nef in Infected Cells and by Nef Transfer to Bystander Cells

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Muratori, Claudia, Cavallin, Lucas E., Krätzel, Kirsten, Tinari, Antonella, De Milito, Angelo, Fais, Stefano, D'Aloja, Paola, Federico, Maurizio +5 more·2009·Cell Host & Microbe

DOI 10.1016/j.chom.2009.06.009

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Abstract

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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Egorov, I. K. (2005) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-005-0007-8 · Cited by 18 · see citing works
Effects of CD45 on NF-kappa B. Implications for replication of HIV-1.
Baur, A. S., Garber, S., & Peterlin, B. M. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.3.976 · Cited by 17 · see citing works
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Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication
Mathieu, M., Jaular, L. M., Lavieu, G., & Théry, C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0250-9 · Cited by 3,776 · see citing works
Standardization of sample collection, isolation and analysis methods in extracellular vesicle research
Witwer, K. W., Buzás, E. I., Bemis, L., Bora, A., Lässer, C., Lötvall, J. O., Hoen, E. N. M. N., Piper, M. G., Sivaraman, S., Skog, J., et al. (2013) · Journal of Extracellular Vesicles · doi:10.3402/jev.v2i0.20360 · Cited by 2,424 · see citing works
Microvesicles and Viral Infection
Meckes, D. G., & Raab‐Traub, N. (2011) · Journal of Virology · doi:10.1128/jvi.05853-11 · Cited by 389 · see citing works
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 · see citing works
Exosomes: Implications in HIV-1 Pathogenesis
Madison, M. N., & Okeoma, C. M. (2015) · Viruses · doi:10.3390/v7072810 · Cited by 175 · see citing works
“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].”
Background
Exosomes from Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Cells License Quiescent CD4 + T Lymphocytes To Replicate HIV-1 through a Nef- and ADAM17-Dependent Mechanism
Arenaccio, 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 · see citing works
“Exosomes from HIV1-infected cells incorporate Gag (5) and Nef HIV-1 proteins (6, 7).”
BackgroundSelf-citation
Extracellular 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 168 · see citing works
HIV Type 1 Nef Is Released from Infected Cells in CD45 + Microvesicles and Is Present in the Plasma of HIV-Infected Individuals
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 169 · see citing works
“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.”
Result
Biogenesis 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 135 · see citing works
Self-citation
Exosomes containing HIV protein Nef reorganize lipid rafts potentiating inflammatory response in bystander cells
Mukhamedova, 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 132 · see citing works
“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].”
Background
Extracellular 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 · see citing works
“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].”
Background
HIV ‐1 Nef: Taking Control of Protein Trafficking
Pereira, E. A., & daSilva, L. L. P. (2016) · Traffic · doi:10.1111/tra.12412 · Cited by 131 · see citing works
“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.”
BackgroundInfluential
Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides
Raymond, 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 · see citing works
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 114 · see citing works
“In addition to being secreted in exosomes, HIV-1 Nef was previously shown to induce the release of these extracellular vesicles [39, 40].”
BackgroundMethodInfluential
HIV-Nef and ADAM17-Containing Plasma Extracellular Vesicles Induce and Correlate with Immune Pathogenesis in Chronic HIV Infection
Lee, 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 · see citing works
“EV purification was performed essentially as described previously (Muratori et al., 2009; Thery et al., 2009).”
BackgroundMethodResultInfluentialSelf-citation
JC 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 · see citing works
Immunocapture-based ELISA to characterize and quantify exosomes in both cell culture supernatants and body fluids
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 106 · see citing works
Self-citation
Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA
Ferdin, 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 · see citing works
“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.”
Background
Biogenesis 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 · see citing works
“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).”
Background
GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain
Dar, 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 · see citing works
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 100 · see citing works
“Interestingly, Nef transfer between T cells may also occur through exchange of microvesicles or patches of plasma membrane (33).”
Background
Oxygen matters: tissue culture oxygen levels affect mitochondrial function and structure as well as responses to HIV viroproteins
Tiede, L. M., Cook, E. A., Morsey, B., & Fox, H. S. (2011) · Cell Death and Disease · doi:10.1038/cddis.2011.128 · Cited by 99 · see citing works
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 · see citing works
“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-citation
Latent HIV-1 is activated by exosomes from cells infected with either replication-competent or defective HIV-1
Arenaccio, C., Anticoli, S., Manfredi, F., Chiozzini, C., Olivetta, E., & Federico, M. (2015) · Retrovirology · doi:10.1186/s12977-015-0216-y · Cited by 94 · see citing works
“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-citation
Proteomic analysis of HIV-1 Nef cellular binding partners reveals a role for exocyst complex proteins in mediating enhancement of intercellular nanotube formation
Mukerji, J., Olivieri, K. C., Misra, V., Agopian, K. A., & Gabuzda, D. H. (2012) · Retrovirology · doi:10.1186/1742-4690-9-33 · Cited by 92 · see citing works
“Exosomes or microvesicles that contain Nef [24] or proinflammatory molecules such as cytokines [86] contribute to cell activation [25] and activation-induced apoptosis [24].”
BackgroundResultInfluential
HIV-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 91 · see citing works
“Nef has been reported to trigger the release of exosome microvesicles that are massively secreted to bystander cells upon T-cell activation [115,116].”
Background
Association 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 · see citing works
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 88 · see citing works
“exosome biogenesis, the secretion of these vesicles (27),”
Background
Antiretroviral 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 · see citing works
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 · see citing works
JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor
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 81 · see citing works
A strategy of antigen incorporation into exosomes: Comparing cross-presentation levels of antigens delivered by engineered exosomes and by lentiviral virus-like particles
Lattanzi, L., & Federico, M. (2012) · Vaccine · doi:10.1016/j.vaccine.2012.10.010 · Cited by 81 · see citing works
“membrane lipid raft microdomains [14–20].”
BackgroundSelf-citation
HIV-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 76 · see citing works
Transfer of Intracellular HIV Nef to Endothelium Causes Endothelial Dysfunction
Wang, T., Green, L. A., Gupta, S. K., Kim, C., Wang, L., Almodóvar, S., Flores, S. C., Prudovsky, I. A., Jolicoeur, P., Liu, Z., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091063 · Cited by 74 · see citing works
Multifunctional role of exosomes in viral diseases: From transmission to diagnosis and therapy
Chaudhari, P., Ghate, V., Nampoothiri, M., & Lewis, S. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110325 · Cited by 72 · see citing works
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 72 · see citing works
“human and simian immunodeficiency virus has been reported to be incorporated into EVs [89,105,113].”
Background
Unbiased proteomic profiling of host cell extracellular vesicle composition and dynamics upon HIV‐1 infection
Jaular, 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 69 · see citing works
“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).”
Secretion Modification Region-Derived Peptide Disrupts HIV-1 Nef's Interaction with Mortalin and Blocks Virus and Nef Exosome Release
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 · see citing works
“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).”
BackgroundResultInfluential
Fifty 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 · see citing works
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 68 · see citing works
Self-citation
Exosomes 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 65 · see citing works
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 · see citing works
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 66 · see citing works
“Nef also increases the exosome production in HIV-1 infected or Nef-transduced cells [56].”
Cell activation and HIV-1 replication in unstimulated CD4+T lymphocytes ingesting exosomes from cells expressing defective HIV-1
Arenaccio, C., Chiozzini, C., Cabezas, S. C., Manfredi, F., & Federico, M. (2014) · Retrovirology · doi:10.1186/1742-4690-11-46 · Cited by 64 · see citing works
“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-citation
The HIV-1 Nef Protein Binds Argonaute-2 and Functions as a Viral Suppressor of RNA Interference
Aqil, M., Naqvi, A. R., Bano, A. S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074472 · Cited by 65 · see citing works
“This was observed earlier for T cells as well [25,41].”
Background
HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements
Leonard, J. A., Filzen, T. M., Carter, C. C., Schaefer, M. R., & Collins, K. L. (2011) · Journal of Virology · doi:10.1128/jvi.00229-11 · Cited by 65 · see citing works
“Nef might also access CD8 T cells through cell-cell contacts, as was described to occur between infected and bystander T cells (61).”
Background
Sequences 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 · see citing works
“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-citation
Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg
Baur, 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 63 · see citing works
Self-citation
HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network–associated Lck signaling
Pan, X., Rudolph, J. M., Abraham, L., et al. (2011) · Blood · doi:10.1182/blood-2011-08-373209 · Cited by 63 · see citing works
The Antagonism of HIV-1 Nef to SERINC5 Particle Infectivity Restriction Involves the Counteraction of Virion-Associated Pools of the Restriction Factor
Trautz, B., Pierini, V., Wombacher, R., et al. (2016) · Journal of Virology · doi:10.1128/jvi.01246-16 · Cited by 62 · see citing works
“Similar results were obtained upon coexpression of Nef, which has been reported to increase the release of extracellular vesicles (42).”
BackgroundResult
Transmission 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 62 · see citing works
Extracellular vesicles from organoids and 3D culture systems
Abdollahi, S. (2020) · Biotechnology and Bioengineering · doi:10.1002/bit.27606 · Cited by 62 · see citing works
“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).”
Background
Emerging roles of extracellular vesicles in neurodegenerative disorders: focus on HIV-associated neurological complications
Hu, 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 · see citing works
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 61 · see citing works
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 · see citing works
“CIITA cells (Stumptner-Cuvelette et al. 2003), and induces extracellular vesicle (EV) secretion from various cells (Lenassi et al. 2010; Muratori et al. 2009).”
BackgroundResultInfluential
The 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 56 · see citing works
“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].”
Background
The 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 56 · see citing works
“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…”
Background
En 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 · see citing works
“[7], multivesicular spheres [8] and released multivesicular cargo [9].”
Background
Isolation 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 · see citing works
HIV Cell-to-Cell Spread Results in Earlier Onset of Viral Gene Expression by Multiple Infections per Cell
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 51 · see citing works
“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 · see citing works
“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).”
Background
The 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 · see citing works
HIV-1 Nef Induces Proinflammatory State in Macrophages through Its Acidic Cluster Domain: Involvement of TNF Alpha Receptor Associated Factor 2
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 · see citing works
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 · see citing works
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 44 · see citing works
“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.”
Background
Tuning of AKT-pathway by Nef and its blockade by protease inhibitors results in limited recovery in latently HIV infected T-cell line
Kumar, 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 · see citing works
DNA Vectors Generating Engineered Exosomes Potential CTL Vaccine Candidates Against AIDS, Hepatitis B, and Tumors
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 · see citing works
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Cutting Edge: Regulation of Exosome Secretion by the Integral MAL Protein in T Cells
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“Expression of the HIV-1 accessory protein Nef in T cells induces massive secretion of exosome markers (16, 17).”
Background
HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection
Ostalecki, C., Wittki, S., Lee, J., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.10.027 · Cited by 41 · see citing works
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BackgroundMethodResultInfluentialSelf-citation
Nef-induced CCL2 Expression Contributes to HIV/SIV Brain Invasion and Neuronal Dysfunction
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“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).”
Background
Transcriptomic Analysis of mRNAs in Human Monocytic Cells Expressing the HIV-1 Nef Protein and Their Exosomes
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“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].”
Background
The Nef-Like Effect of Murine Leukemia Virus Glycosylated Gag on HIV-1 Infectivity Is Mediated by Its Cytoplasmic Domain and Depends on the AP-2 Adaptor Complex
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Exogenous Nef Is an Inhibitor of Mycobacterium tuberculosis-induced Tumor Necrosis Factor-α Production and Macrophage Apoptosis
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Exosomes Are Unlikely Involved in Intercellular Nef Transfer
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BackgroundResult
Association with PAK2 Enables Functional Interactions of Lentiviral Nef Proteins with the Exocyst Complex
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TIM-mediated inhibition of HIV-1 release is antagonized by Nef but potentiated by SERINC proteins
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“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).”
Background
Non-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 · see citing works
“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).”
Background
Incorporation of Heterologous Proteins in Engineered Exosomes
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Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC
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Alzheimer's disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus
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HIV-1 Nef Enhances Dendritic Cell-Mediated Viral Transmission to CD4+ T Cells and Promotes T-Cell Activation
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“cells to bystander cells upon cell-to-cell contact and contribute to the detrimental effect on bystander cells in viral infection”
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Gift bags from the sentinel cells of the immune system: The diverse role of dendritic cell-derived extracellular vesicles
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Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome
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“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].”
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Ferrantelli, F., Chiozzini, C., Manfredi, F., Giovannelli, A., Leone, P., & Federico, M. (2021) · Vaccines · doi:10.3390/vaccines9030240 · Cited by 25 · see citing works
“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-citation
The 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 · see citing works
HIV-1 Nef Changes the Proteome of T Cells Extracellular Vesicles Depleting IFITMs and Other Antiviral Factors
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 · see citing works
HIV-Nef and AIDS pathogenesis: are we barking up the wrong tree?
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Innate 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 · see citing works
“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-citation
Shedding 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 24 · see citing works
Extracellular vesicles in COVID-19 prognosis, treatment, and vaccination: an update
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HIV-1 Infection and First Line ART Induced Differential Responses in Mitochondria from Blood Lymphocytes and Monocytes: The ANRS EP45 “Aging” Study
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Characterization of Nef expression in different brain regions of SIV-infected macaques
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The Role of Viral Proteins in the Regulation of Exosomes Biogenesis
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Multifunctional Roles of the N-Terminal Region of HIV-1 SF2 Nef Are Mediated by Three Independent Protein Interaction Sites
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“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).”
Background
Mitochondrial dysfunctions in HIV infection and antiviral drug treatment
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Complexities of JC Polyomavirus Receptor-Dependent and -Independent Mechanisms of Infection
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Spotlight on HIV-1 Nef: SERINC3 and SERINC5 Identified as Restriction Factors Antagonized by the Pathogenesis Factor
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Background
The Contribution of Extracellular Nef to HIV-Induced Pathogenesis
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Self-citation
Brain Transcriptome-Wide Screen for HIV-1 Nef Protein Interaction Partners Reveals Various Membrane-Associated Proteins
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Background

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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: Muratori, Claudia
Tinari, Antonella
Fais, Stefano
Federico, Maurizio
Fomina, Alla
Mesri, Enrique A.
Superti, Fabiana
Baur, Andreas S.
Venue: Cell Host & Microbe
Publisher: Elsevier BV
Published: 2009-09
Volume: 6
Issue: 3
Pages: 218-230
ISSN: 1931-3128 (ISSN-L)
DOI: 10.1016/j.chom.2009.06.009
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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Massive Secretion by T Cells Is Caused by HIV Nef in Infected Cells and by Nef Transfer to Bystander Cells

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