J. Exp. Med., Volume 188, Number 1, July 1, 1998 83-91

Induction of HIV-1 Replication in Latently Infected CD4⁺ T Cells Using a Combination of Cytokines

By Tae-Wook Chun, Delphine Engel, Stephanie B. Mizell, Linda A. Ehler, and Anthony S. Fauci

From the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in peripheral blood mononuclear cells (PBMCs) of HIV-1-infected individuals, it is unclear what role these cytokines play in the induction of HIV-1 replication in latently infected, resting CD4⁺ T cells. This study demonstrates that the in vitro combination of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)- together with the immunoregulatory cytokine IL-2 are potent inducers of viral replication in highly purified, latently infected, resting CD4⁺ T cells derived from HIV-infected individuals who are antiretroviral therapy-naive as well as those who are receiving highly active antiretroviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vitro. Given that an array of cytokines, including IL-6, TNF-, and IL-2, are copiously expressed in the microenvironment of the lymphoid tissues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART was discontinued. Moreover, since it is likely that these infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART.

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

This article has been cited by other articles:

• Crotti, A., Lusic, M., Lupo, R., Lievens, P. M. J., Liboi, E., Chiara, G. D., Tinelli, M., Lazzarin, A., Patterson, B. K., Giacca, M., Bovolenta, C., Poli, G. (2007). Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression. Blood 109: 5380-5389 [Abstract] [Full Text]  
• Shen, A., Yang, H.-C., Zhou, Y., Chase, A. J., Boyer, J. D., Zhang, H., Margolick, J. B., Zink, M. C., Clements, J. E., Siliciano, R. F. (2007). Novel Pathway for Induction of Latent Virus from Resting CD4+ T Cells in the Simian Immunodeficiency Virus/Macaque Model of Human Immunodeficiency Virus Type 1 Latency. J. Virol. 81: 1660-1670 [Abstract] [Full Text]  
• Oguariri, R. M., Brann, T. W., Imamichi, T. (2007). Hydroxyurea and Interleukin-6 Synergistically Reactivate HIV-1 Replication in a Latently Infected Promonocytic Cell Line via SP1/SP3 Transcription Factors. J. Biol. Chem. 282: 3594-3604 [Abstract] [Full Text]  
• Yamamoto, T., Miyoshi, H., Yamamoto, N., Yamamoto, N., Inoue, J.-i., Tsunetsugu-Yokota, Y. (2006). Lentivirus vectors expressing short hairpin RNAs against the U3-overlapping region of HIV nef inhibit HIV replication and infectivity in primary macrophages. Blood 108: 3305-3312 [Abstract] [Full Text]  
• Cassol, E., Alfano, M., Biswas, P., Poli, G. (2006). Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence. J. Leukoc. Biol. 80: 1018-1030 [Abstract] [Full Text]  
• Schlaepfer, E., Audige, A., Joller, H., Speck, R. F. (2006). TLR7/8 Triggering Exerts Opposing Effects in Acute versus Latent HIV Infection.. J. Immunol. 176: 2888-2895 [Abstract] [Full Text]  
• Rizzi, C., Crippa, M. P., Jeeninga, R. E., Berkhout, B., Blasi, F., Poli, G., Alfano, M. (2006). Pertussis Toxin B-Oligomer Suppresses IL-6 Induced HIV-1 and Chemokine Expression in Chronically Infected U1 Cells via Inhibition of Activator Protein 1. J. Immunol. 176: 999-1006 [Abstract] [Full Text]  
• Swiggard, W. J., Baytop, C., Yu, J. J., Dai, J., Li, C., Schretzenmair, R., Theodosopoulos, T., O'Doherty, U. (2005). Human Immunodeficiency Virus Type 1 Can Establish Latent Infection in Resting CD4+ T Cells in the Absence of Activating Stimuli. J. Virol. 79: 14179-14188 [Abstract] [Full Text]  
• Lee, C., Tomkowicz, B., Freedman, B. D., Collman, R. G. (2005). HIV-1 gp120-induced TNF-{alpha} production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways. J. Leukoc. Biol. 78: 1016-1023 [Abstract] [Full Text]  
• Sung, H., Kang, S.-M., Lee, M.-S., Kim, T. G., Cho, Y.-K. (2005). Korean Red Ginseng Slows Depletion of CD4 T Cells in Human Immunodeficiency Virus Type 1-Infected Patients. CVI 12: 497-501 [Abstract] [Full Text]  
• Devadas, K., Hardegen, N. J., Wahl, L. M., Hewlett, I. K., Clouse, K. A., Yamada, K. M., Dhawan, S. (2004). Mechanisms for Macrophage-Mediated HIV-1 Induction. J. Immunol. 173: 6735-6744 [Abstract] [Full Text]  
• Equils, O., Shapiro, A., Madak, Z., Liu, C., Lu, D. (2004). Human Immunodeficiency Virus Type 1 Protease Inhibitors Block Toll-Like Receptor 2 (TLR2)- and TLR4-Induced NF-{kappa}B Activation. Antimicrob. Agents Chemother. 48: 3905-3911 [Abstract] [Full Text]  
• Fondere, J.-M., Petitjean, G., Huguet, M.-F., Salhi, S. L., Baillat, V., Macura-Biegum, A., Becquart, P., Reynes, J., Vendrell, J.-P. (2004). Human Immunodeficiency Virus Type 1 (HIV-1) Antigen Secretion by Latently Infected Resting CD4+ T Lymphocytes from HIV-1-Infected Individuals. J. Virol. 78: 10536-10542 [Abstract] [Full Text]  
• Lassen, K. G., Bailey, J. R., Siliciano, R. F. (2004). Analysis of Human Immunodeficiency Virus Type 1 Transcriptional Elongation in Resting CD4+ T Cells In Vivo. J. Virol. 78: 9105-9114 [Abstract] [Full Text]  
• Han, Y., Lassen, K., Monie, D., Sedaghat, A. R., Shimoji, S., Liu, X., Pierson, T. C., Margolick, J. B., Siliciano, R. F., Siliciano, J. D. (2004). Resting CD4+ T Cells from Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals Carry Integrated HIV-1 Genomes within Actively Transcribed Host Genes. J. Virol. 78: 6122-6133 [Abstract] [Full Text]  
• Barat, C., Gervais, P., Tremblay, M. J. (2004). Engagement of ICAM-3 Provides a Costimulatory Signal for Human Immunodeficiency Virus Type 1 Replication in both Activated and Quiescent CD4+ T Lymphocytes: Implications for Virus Pathogenesis. J. Virol. 78: 6692-6697 [Abstract] [Full Text]  
• Scheller, C., Ullrich, A., McPherson, K., Hefele, B., Knoferle, J., Lamla, S., Olbrich, A. R. M., Stocker, H., Arasteh, K., Meulen, V. t., Rethwilm, A., Koutsilieri, E., Dittmer, U. (2004). CpG Oligodeoxynucleotides Activate HIV Replication in Latently Infected Human T Cells. J. Biol. Chem. 279: 21897-21902 [Abstract] [Full Text]  
• Audige, A., Schlaepfer, E., Bonanomi, A., Joller, H., Knuchel, M. C., Weber, M., Nadal, D., Speck, R. F. (2004). HIV-1 Does Not Provoke Alteration of Cytokine Gene Expression in Lymphoid Tissue after Acute Infection Ex Vivo. J. Immunol. 172: 2687-2696 [Abstract] [Full Text]  
• Brooks, D. G., Arlen, P. A., Gao, L., Kitchen, C. M. R., Zack, J. A. (2003). Identification of T cell-signaling pathways that stimulate latent HIV in primary cells. Proc. Natl. Acad. Sci. USA 100: 12955-12960 [Abstract] [Full Text]  
• Hamer, D. H., Bocklandt, S., McHugh, L., Chun, T.-W., Blumberg, P. M., Sigano, D. M., Marquez, V. E. (2003). Rational Design of Drugs That Induce Human Immunodeficiency Virus Replication. J. Virol. 77: 10227-10236 [Abstract] [Full Text]  
• Lin, X., Irwin, D., Kanazawa, S., Huang, L., Romeo, J., Yen, T. S. B., Peterlin, B. M. (2003). Transcriptional Profiles of Latent Human Immunodeficiency Virus in Infected Individuals: Effects of Tat on the Host and Reservoir. J. Virol. 77: 8227-8236 [Abstract] [Full Text]  
• Strain, M. C., Gunthard, H. F., Havlir, D. V., Ignacio, C. C., Smith, D. M., Leigh-Brown, A. J., Macaranas, T. R., Lam, R. Y., Daly, O. A., Fischer, M., Opravil, M., Levine, H., Bacheler, L., Spina, C. A., Richman, D. D., Wong, J. K. (2003). Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence. Proc. Natl. Acad. Sci. USA 100: 4819-4824 [Abstract] [Full Text]  
• Pion, M., Jordan, A., Biancotto, A., Dequiedt, F., Gondois-Rey, F., Rondeau, S., Vigne, R., Hejnar, J., Verdin, E., Hirsch, I. (2003). Transcriptional Suppression of In Vitro-Integrated Human Immunodeficiency Virus Type 1 Does Not Correlate with Proviral DNA Methylation. J. Virol. 77: 4025-4032 [Abstract] [Full Text]  
• Kinter, A. L., Umscheid, C. A., Arthos, J., Cicala, C., Lin, Y., Jackson, R., Donoghue, E., Ehler, L., Adelsberger, J., Rabin, R. L., Fauci, A. S. (2003). HIV Envelope Induces Virus Expression from Resting CD4+ T Cells Isolated from HIV-Infected Individuals in the Absence of Markers of Cellular Activation or Apoptosis. J. Immunol. 170: 2449-2455 [Abstract] [Full Text]  
• Scripture-Adams, D. D., Brooks, D. G., Korin, Y. D., Zack, J. A. (2002). Interleukin-7 Induces Expression of Latent Human Immunodeficiency Virus Type 1 with Minimal Effects on T-Cell Phenotype. J. Virol. 76: 13077-13082 [Abstract] [Full Text]  
• Quivy, V., Adam, E., Collette, Y., Demonte, D., Chariot, A., Vanhulle, C., Berkhout, B., Castellano, R., de Launoit, Y., Burny, A., Piette, J., Bours, V., Van Lint, C. (2002). Synergistic Activation of Human Immunodeficiency Virus Type 1 Promoter Activity by NF-{kappa}B and Inhibitors of Deacetylases: Potential Perspectives for the Development of Therapeutic Strategies. J. Virol. 76: 11091-11103 [Abstract] [Full Text]  
• Korin, Y. D., Brooks, D. G., Brown, S., Korotzer, A., Zack, J. A. (2002). Effects of Prostratin on T-Cell Activation and Human Immunodeficiency Virus Latency. J. Virol. 76: 8118-8123 [Abstract] [Full Text]  
• Scheller, C., Sopper, S., Chen, P., Flory, E., Koutsilieri, E., Racek, T., Ludwig, S., ter Meulen, V., Jassoy, C. (2002). Caspase Inhibition Activates HIV in Latently Infected Cells. ROLE OF TUMOR NECROSIS FACTOR RECEPTOR 1 AND CD95. J. Biol. Chem. 277: 15459-15464 [Abstract] [Full Text]  
• van Rij, R. P., Visser, J. A., van Praag, R. M. E., Rientsma, R., Prins, J. M., Lange, J. M. A., Schuitemaker, H. (2002). Both R5 and X4 Human Immunodeficiency Virus Type 1 Variants Persist during Prolonged Therapy with Five Antiretroviral Drugs. J. Virol. 76: 3054-3058 [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]  
• Ghose, R., Liou, L.-Y., Herrmann, C. H., Rice, A. P. (2001). Induction of TAK (Cyclin T1/P-TEFb) in Purified Resting CD4+ T Lymphocytes by Combination of Cytokines. J. Virol. 75: 11336-11343 [Abstract] [Full Text]  
• Lawn, S. D., Butera, S. T., Folks, T. M. (2001). Contribution of Immune Activation to the Pathogenesis and Transmission of Human Immunodeficiency Virus Type 1 Infection. Clin. Microbiol. Rev. 14: 753-777 [Abstract] [Full Text]  
• Scales, D., Ni, H., Shaheen, F., Capodici, J., Cannon, G., Weissman, D. (2001). Nonproliferating Bystander CD4+ T Cells Lacking Activation Markers Support HIV Replication During Immune Activation. J. Immunol. 166: 6437-6443 [Abstract] [Full Text]  
• Orandle, M. S., Williams, K. C., MacLean, A. G., Westmoreland, S. V., Lackner, A. A. (2001). Macaques with Rapid Disease Progression and Simian Immunodeficiency Virus Encephalitis Have a Unique Cytokine Profile in Peripheral Lymphoid Tissues. J. Virol. 75: 4448-4452 [Abstract] [Full Text]  
• Veazey, R. S., Mansfield, K. G., Tham, I. C., Carville, A. C., Shvetz, D. E., Forand, A. E., Lackner, A. A. (2000). Dynamics of CCR5 Expression by CD4+ T Cells in Lymphoid Tissues during Simian Immunodeficiency Virus Infection. J. Virol. 74: 11001-11007 [Abstract] [Full Text]  
• Crowe, S. M., Sonza, S. (2000). HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication. J. Leukoc. Biol. 68: 345-350 [Abstract] [Full Text]  
• Ledru, E., Christeff, N., Patey, O., de Truchis, P., Melchior, J.-C., Gougeon, M.-L. (2000). Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. Blood 95: 3191-3198 [Abstract] [Full Text]  
• Veazey, R. S., Tham, I. C., Mansfield, K. G., DeMaria, M., Forand, A. E., Shvetz, D. E., Chalifoux, L. V., Sehgal, P. K., Lackner, A. A. (2000). Identifying the Target Cell in Primary Simian Immunodeficiency Virus (SIV) Infection: Highly Activated Memory CD4+ T Cells Are Rapidly Eliminated in Early SIV Infection In Vivo. J. Virol. 74: 57-64 [Abstract] [Full Text]  
• Davey, R. T. Jr., Bhat, N., Yoder, C., Chun, T.-W., Metcalf, J. A., Dewar, R., Natarajan, V., Lempicki, R. A., Adelsberger, J. W., Miller, K. D., Kovacs, J. A., Polis, M. A., Walker, R. E., Falloon, J., Masur, H., Gee, D., Baseler, M., Dimitrov, D. S., Fauci, A. S., Lane, H. C. (1999). HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natl. Acad. Sci. USA 96: 15109-15114 [Abstract] [Full Text]  
• Ferguson, N. M., deWolf, F., Ghani, A. C., Fraser, C., Donnelly, C. A., Reiss, P., Lange, J. M. A., Danner, S. A., Garnett, G. P., Goudsmit, J., Anderson, R. M. (1999). Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 96: 15167-15172 [Abstract] [Full Text]  
• Highbarger, H. C., Alvord, W. G., Jiang, M. K., Shah, A. S., Metcalf, J. A., Lane, H. C., Dewar, R. L. (1999). Comparison of the Quantiplex Version 3.0 Assay and a Sensitized Amplicor Monitor Assay for Measurement of Human Immunodeficiency Virus Type 1 RNA Levels in Plasma Samples. J. Clin. Microbiol. 37: 3612-3614 [Abstract] [Full Text]  
• Muto, N. F., Martinand-Mari, C., Adelson, M. E., Suhadolnik, R. J. (1999). Inhibition of Replication of Reactivated Human Immunodeficiency Virus Type 1 (HIV-1) in Latently Infected U1 Cells Transduced with an HIV-1 Long Terminal Repeat-Driven PKR cDNA Construct. J. Virol. 73: 9021-9028 [Abstract] [Full Text]  
• Chun, T.-W., Fauci, A. S. (1999). Latent reservoirs of HIV: Obstacles to the eradication of virus. Proc. Natl. Acad. Sci. USA 96: 10958-10961 [Full Text]  
• Yang, X., Chen, Y., Gabuzda, D. (1999). ERK MAP Kinase Links Cytokine Signals to Activation of Latent HIV-1 Infection by Stimulating a Cooperative Interaction of AP-1 and NF-kappa B. J. Biol. Chem. 274: 27981-27988 [Abstract] [Full Text]  
• Vicenzi, E., Bordignon, P. P., Biswas, P., Brambilla, A., Bovolenta, C., Cota, M., Sinigaglia, F., Poli, G. (1999). Envelope-Dependent Restriction of Human Immunodeficiency Virus Type 1 Spreading in CD4+ T Lymphocytes: R5 but Not X4 Viruses Replicate in the Absence of T-Cell Receptor Restimulation. J. Virol. 73: 7515-7523 [Abstract] [Full Text]  
• Unutmaz, D., KewalRamani, V. N., Marmon, S., Littman, D. R. (1999). Cytokine Signals Are Sufficient for HIV-1 Infection of Resting Human T Lymphocytes. J. Exp. Med. 189: 1735-1746 [Abstract] [Full Text]  
• Cohen, O. J., Fauci, A. S. (1998). HIV/AIDS in 1998--Gaining the Upper Hand?. JAMA 280: 87-88 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS