J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/07/7/10 $2.00
Volume 186, Number 1, July 7, 1997 7-16

Evasion of Cytotoxic T Lymphocyte (CTL) Responses by Nef-dependent Induction of Fas Ligand (CD95L) Expression on Simian Immunodeficiency Virus-infected Cells

By Xiao-Ning Xu,^* Gavin R. Screaton,^* Frances M. Gotch, Tao Dong,^* Rusung Tan,^* Neil Almond,^§ Barry Walker,^§ Richard Stebbings,^§ Karen Kent,^§ Shigekazu Nagata, Jim E. Stott,^§ and Andrew J. McMichael^*

From the ^* Molecular Immunology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; the   Dept of Immunology, Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; the ^§ AIDS Collaborating Centre, National Institute for Biological Standards and Control, Hertfordshire EN6 3QG, United Kingdom; the  Department of Genetics, Osaka University Medical School, Osaka 565, Japan

Inoculation of macaques with live attenuated SIV strains has been shown to protect against subsequent challenge with wild-type SIV. The protective mechanism(s) remain obscure. To study the effect in more detail, we have investigated the role of virus-specific CTL responses in macaques infected with an attenuated SIV strain (pC8), which has a four-amino acid deletion in the nef gene, as compared with the wild-type SIVmac32H clone (pJ5). Cynomolgus macaques infected with pC8 were protected against subsequent challenge with pJ5 and did not develop any AIDS-like symptoms in the 12 months after infection. The pC8-induced protection was associated with high levels of virus-specific CTL responses to a variety of viral antigens. In contrast, pJ5-infected macaques had little, if any, detectable CTL response to the viral proteins after three months. The latter group of macaques also showed increased Fas expression and apoptotic cell death in both the CD4⁺ and CD8⁺ populations. In vitro, pJ5 but not pC8 leads to an increase in FasL expression on infected cells. Thus the expression of FasL may protect infected cells from CTL attack, killing viral-specific CTLs in the process, and providing a route for escaping the immune response, leading to the increased pathogenicity of pJ5. pC8, on the other hand does not induce FasL expression, allowing the development of a protective CTL response. Furthermore, interruption of the Fas-FasL interaction allows the regeneration of viral-specific CTL responses in pJ5-infected animals. This observation suggests an additional therapeutic approach to the treatment of AIDS.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Gasper-Smith, N., Crossman, D. M., Whitesides, J. F., Mensali, N., Ottinger, J. S., Plonk, S. G., Moody, M. A., Ferrari, G., Weinhold, K. J., Miller, S. E., Reich, C. F. III, Qin, L., Self, S. G., Shaw, G. M., Denny, T. N., Jones, L. E., Pisetsky, D. S., Haynes, B. F. (2008). Induction of Plasma (TRAIL), TNFR-2, Fas Ligand, and Plasma Microparticles after Human Immunodeficiency Virus Type 1 (HIV-1) Transmission: Implications for HIV-1 Vaccine Design. J. Virol. 82: 7700-7710 [Abstract] [Full Text]  
• Mueller, Y. M., Petrovas, C., Do, D. H., Altork, S. R., Fischer-Smith, T., Rappaport, J., Altman, J. D., Lewis, M. G., Katsikis, P. D. (2007). Early Establishment and Antigen Dependence of Simian Immunodeficiency Virus-Specific CD8+ T-Cell Defects. J. Virol. 81: 10861-10868 [Abstract] [Full Text]  
• Majumder, B., Venkatachari, N. J., Schafer, E. A., Janket, M. L., Ayyavoo, V. (2007). Dendritic Cells Infected with vpr-Positive Human Immunodeficiency Virus Type 1 Induce CD8+ T-Cell Apoptosis via Upregulation of Tumor Necrosis Factor Alpha. J. Virol. 81: 7388-7399 [Abstract] [Full Text]  
• Mangino, G., Percario, Z. A., Fiorucci, G., Vaccari, G., Manrique, S., Romeo, G., Federico, M., Geyer, M., Affabris, E. (2007). In Vitro Treatment of Human Monocytes/Macrophages with Myristoylated Recombinant Nef of Human Immunodeficiency Virus Type 1 Leads to the Activation of Mitogen-Activated Protein Kinases, I{kappa}B Kinases, and Interferon Regulatory Factor 3 and to the Release of Beta Interferon. J. Virol. 81: 2777-2791 [Abstract] [Full Text]  
• Iannello, A., Debbeche, O., Martin, E., Attalah, L. H., Samarani, S., Ahmad, A. (2006). Viral strategies for evading antiviral cellular immune responses of the host. J. Leukoc. Biol. 79: 16-35 [Abstract] [Full Text]  
• Hel, Z., Tsai, W.-P., Tryniszewska, E., Nacsa, J., Markham, P. D., Lewis, M. G., Pavlakis, G. N., Felber, B. K., Tartaglia, J., Franchini, G. (2006). Improved Vaccine Protection from Simian AIDS by the Addition of Nonstructural Simian Immunodeficiency Virus Genes. J. Immunol. 176: 85-96 [Abstract] [Full Text]  
• Priceputu, E., Rodrigue, I., Chrobak, P., Poudrier, J., Mak, T. W., Hanna, Z., Hu, C., Kay, D. G., Jolicoeur, P. (2005). The Nef-Mediated AIDS-Like Disease of CD4C/Human Immunodeficiency Virus Transgenic Mice Is Associated with Increased Fas/FasL Expression on T Cells and T-Cell Death but Is Not Prevented in Fas-, FasL-, Tumor Necrosis Factor Receptor 1-, or Interleukin-1{beta}-Converting Enzyme-Deficient or Bcl2-Expressing Transgenic Mice. J. Virol. 79: 6377-6391 [Abstract] [Full Text]  
• Schindler, M., Munch, J., Kirchhoff, F. (2005). Human Immunodeficiency Virus Type 1 Inhibits DNA Damage-Triggered Apoptosis by a Nef-Independent Mechanism. J. Virol. 79: 5489-5498 [Abstract] [Full Text]  
• Lee, S. B., Park, J., Jung, J. U., Chung, J. (2005). Nef induces apoptosis by activating JNK signaling pathway and inhibits NF-{kappa}B-dependent immune responses in Drosophila. J. Cell Sci. 118: 1851-1859 [Abstract] [Full Text]  
• Acheampong, E. A., Parveen, Z., Muthoga, L. W., Kalayeh, M., Mukhtar, M., Pomerantz, R. J. (2005). Human Immunodeficiency Virus Type 1 Nef Potently Induces Apoptosis in Primary Human Brain Microvascular Endothelial Cells via the Activation of Caspases. J. Virol. 79: 4257-4269 [Abstract] [Full Text]  
• Dong, T., Stewart-Jones, G., Chen, N., Easterbrook, P., Xu, X., Papagno, L., Appay, V., Weekes, M., Conlon, C., Spina, C., Little, S., Screaton, G., van der Merwe, A., Richman, D. D., McMichael, A. J., Jones, E. Y., Rowland-Jones, S. L. (2004). HIV-specific Cytotoxic T Cells from Long-Term Survivors Select a Unique T Cell Receptor. JEM 200: 1547-1557 [Abstract] [Full Text]  
• Swigut, T., Alexander, L., Morgan, J., Lifson, J., Mansfield, K. G., Lang, S., Johnson, R. P., Skowronski, J., Desrosiers, R. (2004). Impact of Nef-Mediated Downregulation of Major Histocompatibility Complex Class I on Immune Response to Simian Immunodeficiency Virus. J. Virol. 78: 13335-13344 [Abstract] [Full Text]  
• Ropers, D., Ayadi, L., Gattoni, R., Jacquenet, S., Damier, L., Branlant, C., Stevenin, J. (2004). Differential Effects of the SR Proteins 9G8, SC35, ASF/SF2, and SRp40 on the Utilization of the A1 to A5 Splicing Sites of HIV-1 RNA. J. Biol. Chem. 279: 29963-29973 [Abstract] [Full Text]  
• Price, D. A., Scullard, G., Oxenius, A., Braganza, R., Beddows, S. A., Kazmi, S., Clarke, J. R., Johnson, G. E., Weber, J. N., Phillips, R. E. (2003). Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity. J. Virol. 77: 6041-6049 [Abstract] [Full Text]  
• Spetz, A.-L., Sorensen, A. S., Walther-Jallow, L., Wahren, B., Andersson, J., Holmgren, L., Hinkula, J. (2002). Induction of HIV-1-Specific Immunity After Vaccination with Apoptotic HIV-1/Murine Leukemia Virus-Infected Cells. J. Immunol. 169: 5771-5779 [Abstract] [Full Text]  
• Yang, Y., Dong, B., Mittelstadt, P. R., Xiao, H., Ashwell, J. D. (2002). HIV Tat Binds Egr Proteins and Enhances Egr-dependent Transactivation of the Fas Ligand Promoter. J. Biol. Chem. 277: 19482-19487 [Abstract] [Full Text]  
• Brooks, D. G., Zack, J. A. (2002). Effect of Latent Human Immunodeficiency Virus Infection on Cell Surface Phenotype. J. Virol. 76: 1673-1681 [Abstract] [Full Text]  
• Rasola, A., Gramaglia, D., Boccaccio, C., Comoglio, P. M. (2001). Apoptosis Enhancement by the HIV-1 Nef Protein. J. Immunol. 166: 81-88 [Abstract] [Full Text]  
• Badley, A. D., Pilon, A. A., Landay, A., Lynch, D. H. (2000). Mechanisms of HIV-associated lymphocyte apoptosis. Blood 96: 2951-2964 [Abstract] [Full Text]  
• Rosenzweig, M., Connole, M., Forand-Barabasz, A., Tremblay, M.-P., Johnson, R. P., Lackner, A. A. (2000). Mechanisms Associated with Thymocyte Apoptosis Induced by Simian Immunodeficiency Virus. J. Immunol. 165: 3461-3468 [Abstract] [Full Text]  
• Sewell, A. K., Price, D. A., Oxenius, A., Kelleher, A. D., Phillips, R. E. (2000). Cytotoxic T Lymphocyte Responses to Human Immunodeficiency Virus: Control and Escape. Stem Cells 18: 230-244 [Abstract] [Full Text]  
• Micoli, K. J., Pan, G., Wu, Y., Williams, J. P., Cook, W. J., McDonald, J. M. (2000). Requirement of Calmodulin Binding by HIV-1 gp160 for Enhanced FAS-mediated Apoptosis. J. Biol. Chem. 275: 1233-1240 [Abstract] [Full Text]  
• Gauduin, M.-C., Glickman, R. L., Ahmad, S., Yilma, T., Johnson, R. P. (1999). Immunization with live attenuated simian immunodeficiency virus induces strong type 1 T helper responses and beta -chemokine production. Proc. Natl. Acad. Sci. USA 96: 14031-14036 [Abstract] [Full Text]  
• Shankar, P., Xu, Z., Lieberman, J. (1999). Viral-Specific Cytotoxic T Lymphocytes Lyse Human Immunodeficiency Virus-Infected Primary T Lymphocytes by the Granule Exocytosis Pathway. Blood 94: 3084-3093 [Abstract] [Full Text]  
• Hodge, S., de Rosayro, J., Glenn, A., Ojukwu, I. C., Dewhurst, S., McClure, H. M., Bischofberger, N., Anderson, D. C., Klumpp, S. A., Novembre, F. J. (1999). Postinoculation PMPA Treatment, but Not Preinoculation Immunomodulatory Therapy, Protects against Development of Acute Disease Induced by the Unique Simian Immunodeficiency Virus SIVsmmPBj. J. Virol. 73: 8630-8639 [Abstract] [Full Text]  
• M. McKinney, D., Lewinsohn, D. A., Riddell, S. R., Greenberg, P. D., Mosier, D. E. (1999). The Antiviral Activity of HIV-Specific CD8+ CTL Clones Is Limited by Elimination Due to Encounter with HIV-Infected Targets. J. Immunol. 163: 861-867 [Abstract] [Full Text]  
• Xu, X.-N., Laffert, B., Screaton, G. R., Kraft, M., Wolf, D., Kolanus, W., Mongkolsapay, J., McMichael, A. J., Baur, A. S. (1999). Induction of Fas Ligand Expression by HIV Involves the Interaction of Nef with the T Cell Receptor zeta  Chain. JEM 189: 1489-1496 [Abstract] [Full Text]  
• Rich, R. F., Green, W. R. (1999). Antiretroviral Cytolytic T-Lymphocyte Nonresponsiveness: FasL/Fas-Mediated Inhibition of CD4+ and CD8+ Antiviral T Cells by Viral Antigen-Positive Veto Cells. J. Virol. 73: 3826-3834 [Abstract] [Full Text]  
• Tan, R., Xu, X., Ogg, G. S., Hansasuta, P., Dong, T., Rostron, T., Luzzi, G., Conlon, C. P., Screaton, G. R., McMichael, A. J., Rowland-Jones, S. (1999). Rapid Death of Adoptively Transferred T Cells in Acquired Immunodeficiency Syndrome. Blood 93: 1506-1510 [Abstract] [Full Text]  
• Zauli, G., Gibellini, D., Secchiero, P., Dutartre, H., Olive, D., Capitani, S., Collette, Y. (1999). Human Immunodeficiency Virus Type 1 Nef Protein Sensitizes CD4+ T Lymphoid Cells to Apoptosis via Functional Upregulation of the CD95/CD95 Ligand Pathway. Blood 93: 1000-1010 [Abstract] [Full Text]  
• Rivera, I., Harhaj, E. W., Sun, S.-C. (1998). Involvement of NF-AT in Type I Human T-cell Leukemia Virus Tax-mediated Fas Ligand Promoter Transactivation. J. Biol. Chem. 273: 22382-22388 [Abstract] [Full Text]  
• Kaplan, D., Sieg, S. (1998). Role of the Fas/Fas Ligand Apoptotic Pathway in Human Immunodeficiency Virus Type 1 Disease. J. Virol. 72: 6279-6282 [Full Text]  
• Gauduin, M.-C., Glickman, R. L., Means, R., Johnson, R. P. (1998). Inhibition of Simian Immunodeficiency Virus (SIV) Replication by CD8+ T Lymphocytes from Macaques Immunized with Live Attenuated SIV. J. Virol. 72: 6315-6324 [Abstract] [Full Text]  
• Rivoltini, L., Radrizzani, M., Accornero, P., Squarcina, P., Chiodoni, C., Mazzocchi, A., Castelli, C., Tarsini, P., Viggiano, V., Belli, F., Colombo, M. P., Parmiani, G. (1998). Human Melanoma-Reactive CD4+ and CD8+ CTL Clones Resist Fas Ligand-Induced Apoptosis and Use Fas/Fas Ligand-Independent Mechanisms for Tumor Killing. J. Immunol. 161: 1220-1230 [Abstract] [Full Text]  
• Davis, I. C., Girard, M., Fultz, P. N. (1998). Loss of CD4+ T Cells in Human Immunodeficiency Virus Type 1-Infected Chimpanzees Is Associated with Increased Lymphocyte Apoptosis. J. Virol. 72: 4623-4632 [Abstract] [Full Text]  
• Rosenzweig, M., DeMaria, M., Harper, D. M., Friedrich, S., Jain, R. K., Johnson, R. P. (1998). Increased rates of CD4+ and CD8+ T lymphocyte turnover in simian immunodeficiency virus-infected macaques. Proc. Natl. Acad. Sci. USA 95: 6388-6393 [Abstract] [Full Text]  
• Zhang, H.-G., Bilbao, G., Zhou, T., Contreras, J. L., Gomez-Navarro, J., Feng, M., Saito, I., Mountz, J. D., Curiel, D. T. (1998). Application of a Fas Ligand Encoding a Recombinant Adenovirus Vector for Prolongation of Transgene Expression. J. Virol. 72: 2483-2490 [Abstract] [Full Text]  
• Smyth, M. J., Trapani, J. A. (1998). The Relative Role of Lymphocyte Granule Exocytosis versus Death Receptor-Mediated Cytotoxicity in Viral Pathophysiology. J. Virol. 72: 1-9 [Full Text]  
• Johnson, R. P. (1997). Upregulation of Fas Ligand by Simian Immunodeficiency Virus---A nef-arious Mechanism of Immune Evasion?. JEM 186: 1-5 [Full Text]  
• Manninen, A., Herma Renkema, G., Saksela, K. (2000). Synergistic Activation of NFAT by HIV-1 Nef and the Ras/MAPK Pathway. J. Biol. Chem. 275: 16513-16517 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS