This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lundquist, C. A. Articles by Aiken, C. Search for Related Content PubMed PubMed Citation Articles by Lundquist, C. A. Articles by Aiken, C.

 Previous Article  |  Next Article 

Journal of Virology, May 2002, p. 4625-4633, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4625-4633.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Nef-Mediated Downregulation of CD4 Enhances Human Immunodeficiency Virus Type 1 Replication in Primary T Lymphocytes

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363

Received 9 November 2001/ Accepted 25 January 2002

The accessory protein Nef plays a crucial role in primate lentivirus pathogenesis. Nef enhances human immunodeficiency virus type 1 (HIV-1) infectivity in culture and stimulates viral replication in primary T cells. In this study, we investigated the relationship between HIV-1 replication efficiency in CD4⁺ T cells purified from human blood and two various known activities of Nef, CD4 downregulation and single-cycle infectivity enhancement. Using a battery of reporter viruses containing point mutations in nef, we observed a strong genetic correlation between CD4 downregulation by Nef during acute HIV-1 infection of activated T cells and HIV-1 replication efficiency in T cells. In contrast, HIV-1 replication ability was not significantly correlated with the ability of Nef to enhance single-cycle virion infectivity, as determined by using viruses produced in cells lacking CD4. These results demonstrate that CD4 downregulation by Nef plays a crucial role in HIV-1 replication in activated T cells and underscore the potential for the development of therapies targeting this conserved activity of Nef.

This article has been cited by other articles:

• Jin, Y.-J., Cai, C. Y., Zhang, X., Burakoff, S. J. (2008). Lysine 144, a Ubiquitin Attachment Site in HIV-1 Nef, Is Required for Nef-Mediated CD4 Down-Regulation. J. Immunol. 180: 7878-7886 [Abstract] [Full Text]  
• Munch, J., Rajan, D., Schindler, M., Specht, A., Rucker, E., Novembre, F. J., Nerrienet, E., Muller-Trutwin, M. C., Peeters, M., Hahn, B. H., Kirchhoff, F. (2007). Nef-Mediated Enhancement of Virion Infectivity and Stimulation of Viral Replication Are Fundamental Properties of Primate Lentiviruses. J. Virol. 81: 13852-13864 [Abstract] [Full Text]  
• Schindler, M., Rajan, D., Specht, A., Ritter, C., Pulkkinen, K., Saksela, K., Kirchhoff, F. (2007). Association of Nef with p21-Activated Kinase 2 Is Dispensable for Efficient Human Immunodeficiency Virus Type 1 Replication and Cytopathicity in Ex Vivo-Infected Human Lymphoid Tissue. J. Virol. 81: 13005-13014 [Abstract] [Full Text]  
• Noviello, C. M., Pond, S. L. K., Lewis, M. J., Richman, D. D., Pillai, S. K., Yang, O. O., Little, S. J., Smith, D. M., Guatelli, J. C. (2007). Maintenance of Nef-Mediated Modulation of Major Histocompatibility Complex Class I and CD4 after Sexual Transmission of Human Immunodeficiency Virus Type 1. J. Virol. 81: 4776-4786 [Abstract] [Full Text]  
• Crotti, A., Neri, F., Corti, D., Ghezzi, S., Heltai, S., Baur, A., Poli, G., Santagostino, E., Vicenzi, E. (2006). Nef Alleles from Human Immunodeficiency Virus Type 1-Infected Long-Term-Nonprogressor Hemophiliacs with or without Late Disease Progression Are Defective in Enhancing Virus Replication and CD4 Down-Regulation. J. Virol. 80: 10663-10674 [Abstract] [Full Text]  
• Wildum, S., Schindler, M., Munch, J., Kirchhoff, F. (2006). Contribution of vpu, env, and nef to CD4 down-modulation and resistance of human immunodeficiency virus type 1-infected T cells to superinfection.. J. Virol. 80: 8047-8059 [Abstract] [Full Text]  
• Brenner, M., Munch, J., Schindler, M., Wildum, S., Stolte, N., Stahl-Hennig, C., Fuchs, D., Matz-Rensing, K., Franz, M., Heeney, J., Ten Haaft, P., Swigut, T., Hrecka, K., Skowronski, J., Kirchhoff, F. (2006). Importance of the N-Distal AP-2 Binding Element in Nef for Simian Immunodeficiency Virus Replication and Pathogenicity in Rhesus Macaques. J. Virol. 80: 4469-4481 [Abstract] [Full Text]  
• Keppler, O. T., Tibroni, N., Venzke, S., Rauch, S., Fackler, O. T. (2006). Modulation of specific surface receptors and activation sensitization in primary resting CD4+ T lymphocytes by the Nef protein of HIV-1. J. Leukoc. Biol. 79: 616-627 [Abstract] [Full Text]  
• Clay, C. C., Rodrigues, D. S., Harvey, D. J., Leutenegger, C. M., Esser, U. (2005). Distinct Chemokine Triggers and In Vivo Migratory Paths of Fluorescein Dye-Labeled T Lymphocytes in Acutely Simian Immunodeficiency Virus SIVmac251-Infected and Uninfected Macaques. J. Virol. 79: 13759-13768 [Abstract] [Full Text]  
• Brown, A., Gartner, S., Kawano, T., Benoit, N., Cheng-Mayer, C. (2005). HLA-A2 down-regulation on primary human macrophages infected with an M-tropic EGFP-tagged HIV-1 reporter virus. J. Leukoc. Biol. 78: 675-685 [Abstract] [Full Text]  
• Jin, Y.-J., Cai, C. Y., Zhang, X., Zhang, H.-T., Hirst, J. A., Burakoff, S. J. (2005). HIV Nef-Mediated CD4 Down-Regulation Is Adaptor Protein Complex 2 Dependent. J. Immunol. 175: 3157-3164 [Abstract] [Full Text]  
• Munch, J., Schindler, M., Wildum, S., Rucker, E., Bailer, N., Knoop, V., Novembre, F. J., Kirchhoff, F. (2005). Primary Sooty Mangabey Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 2 nef Alleles Modulate Cell Surface Expression of Various Human Receptors and Enhance Viral Infectivity and Replication. J. Virol. 79: 10547-10560 [Abstract] [Full Text]  
• Cluet, D., Bertsch, C., Beyer, C., Gloeckler, L., Erhardt, M., Gut, J.-P., Galzi, J.-L., Aubertin, A.-M. (2005). Detection of Human Immunodeficiency Virus Type 1 Nef and CD4 Physical Interaction in Living Human Cells by Using Bioluminescence Resonance Energy Transfer. J. Virol. 79: 8629-8636 [Abstract] [Full Text]  
• Gillim-Ross, L., Cara, A., Klotman, M. E. (2005). Nef expressed from human immunodeficiency virus type 1 extrachromosomal DNA downregulates CD4 on primary CD4+ T lymphocytes: implications for integrase inhibitors. J. Gen. Virol. 86: 765-771 [Abstract] [Full Text]  
• Pham, H. M., Arganaraz, E. R., Groschel, B., Trono, D., Lama, J. (2004). Lentiviral Vectors Interfering with Virus-Induced CD4 Down-Modulation Potently Block Human Immunodeficiency Virus Type 1 Replication in Primary Lymphocytes. J. Virol. 78: 13072-13081 [Abstract] [Full Text]  
• Jin, Y.-J., Zhang, X., Boursiquot, J. G., Burakoff, S. J. (2004). CD4 Phosphorylation Partially Reverses Nef Down-Regulation of CD4. J. Immunol. 173: 5495-5500 [Abstract] [Full Text]  
• Olszewski, A., Sato, K., Aron, Z. D., Cohen, F., Harris, A., McDougall, B. R., Robinson, W. E. Jr., Overman, L. E., Weiss, G. A. (2004). Guanidine alkaloid analogs as inhibitors of HIV-1 Nef interactions with p53, actin, and p56lck. Proc. Natl. Acad. Sci. USA 101: 14079-14084 [Abstract] [Full Text]  
• Welstead, G. G., Hsu, E. C., Iorio, C., Bolotin, S., Richardson, C. D. (2004). Mechanism of CD150 (SLAM) Down Regulation from the Host Cell Surface by Measles Virus Hemagglutinin Protein. J. Virol. 78: 9666-9674 [Abstract] [Full Text]  
• Rucker, E., Munch, J., Wildum, S., Brenner, M., Eisemann, J., Margolis, L., Kirchhoff, F. (2004). A Naturally Occurring Variation in the Proline-Rich Region Does Not Attenuate Human Immunodeficiency Virus Type 1 Nef Function. J. Virol. 78: 10197-10201 [Abstract] [Full Text]  
• Sol-Foulon, N., Esnault, C., Percherancier, Y., Porrot, F., Metais-Cunha, P., Bachelerie, F., Schwartz, O. (2004). The Effects of HIV-1 Nef on CD4 Surface Expression and Viral Infectivity in Lymphoid Cells Are Independent of Rafts. J. Biol. Chem. 279: 31398-31408 [Abstract] [Full Text]  
• Kirchhoff, F., Schindler, M., Bailer, N., Renkema, G. H., Saksela, K., Knoop, V., Muller-Trutwin, M. C., Santiago, M. L., Bibollet-Ruche, F., Dittmar, M. T., Heeney, J. L., Hahn, B. H., Munch, J. (2004). Nef Proteins from Simian Immunodeficiency Virus-Infected Chimpanzees Interact with p21-Activated Kinase 2 and Modulate Cell Surface Expression of Various Human Receptors. J. Virol. 78: 6864-6874 [Abstract] [Full Text]  
• Lundquist, C. A., Zhou, J., Aiken, C. (2004). Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication. J. Virol. 78: 6287-6296 [Abstract] [Full Text]  
• Brown, A., Moghaddam, S., Kawano, T., Cheng-Mayer, C. (2004). Multiple human immunodeficiency virus type 1 Nef functions contribute to efficient replication in primary human macrophages. J. Gen. Virol. 85: 1463-1469 [Abstract] [Full Text]  
• Costa, L. J., Zheng, Y.-H., Sabotic, J., Mak, J., Fackler, O. T., Peterlin, B. M. (2004). Nef Binds p6* in GagPol during Replication of Human Immunodeficiency Virus Type 1. J. Virol. 78: 5311-5323 [Abstract] [Full Text]  
• Zhou, J., Yuan, X., Dismuke, D., Forshey, B. M., Lundquist, C., Lee, K.-H., Aiken, C., Chen, C. H. (2004). Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation. J. Virol. 78: 922-929 [Abstract] [Full Text]  
• Stumptner-Cuvelette, P., Jouve, M., Helft, J., Dugast, M., Glouzman, A.-S., Jooss, K., Raposo, G., Benaroch, P. (2003). Human Immunodeficiency Virus-1 Nef Expression Induces Intracellular Accumulation of Multivesicular Bodies and Major Histocompatibility Complex Class II Complexes: Potential Role of Phosphatidylinositol 3-Kinase. Mol. Biol. Cell 14: 4857-4870 [Abstract] [Full Text]  
• Casartelli, N., Di Matteo, G., Potesta, M., Rossi, P., Doria, M. (2003). CD4 and Major Histocompatibility Complex Class I Downregulation by the Human Immunodeficiency Virus Type 1 Nef Protein in Pediatric AIDS Progression. J. Virol. 77: 11536-11545 [Abstract] [Full Text]  
• Stove, V., Naessens, E., Stove, C., Swigut, T., Plum, J., Verhasselt, B. (2003). Signaling but not trafficking function of HIV-1 protein Nef is essential for Nef-induced defects in human intrathymic T-cell development. Blood 102: 2925-2932 [Abstract] [Full Text]  
• Arganaraz, E. R., Schindler, M., Kirchhoff, F., Cortes, M. J., Lama, J. (2003). Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication. J. Biol. Chem. 278: 33912-33919 [Abstract] [Full Text]  
• Chakrabarti, L. A., Metzner, K. J., Ivanovic, T., Cheng, H., Louis-Virelizier, J., Connor, R. I., Cheng-Mayer, C. (2002). A Truncated Form of Nef Selected during Pathogenic Reversion of Simian Immunodeficiency Virus SIVmac239{Delta}nef Increases Viral Replication. J. Virol. 77: 1245-1256 [Abstract] [Full Text]  
• Papkalla, A., Munch, J., Otto, C., Kirchhoff, F. (2002). Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity and Replication Independently of Viral Coreceptor Tropism. J. Virol. 76: 8455-8459 [Abstract] [Full Text]