Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF) Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kovacs, J. A. Articles by Lane, H. C. Search for Related Content PubMed PubMed Citation Articles by Kovacs, J. A. Articles by Lane, H. C. Social Bookmarking                      What's this?

¹ Critical Care Medicine Department, Clinical Center
² Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases
³ Laboratory of Experimental and Computational Biology, DBS, National Cancer Institute-Frederick
⁴ Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
⁵ Science Applications International Corporation, Frederick, MD 21702

Address correspondence to Joseph A. Kovacs, Building 10, Rm. 7D43, MSC 1662, Bethesda, MD 20892-1662. Phone: 301-496-9907; Fax: 301-402-1213; E-mail: jkovacs{at}nih.gov

We examined the effects of human immunodeficiency virus infection on the turnover of CD4 and CD8 T lymphocytes in 17 HIV-infected patients by 30 min in vivo pulse labeling with bromodeoxyuridine (BrdU). The percentage of labeled CD4 and CD8 T lymphocytes was initially higher in lymph nodes than in blood. Labeled cells equilibrated between the two compartments within 24 h. Based on mathematical modeling of the dynamics of BrdU-labeled cells in the blood, we identified rapidly and slowly proliferating subpopulations of CD4 and CD8 T lymphocytes. The percentage, but not the decay rate, of labeled CD4 or CD8 cells in the rapidly proliferating pool correlated significantly with plasma HIV RNA levels for both CD4 (r = 0.77, P < 0.001) and CD8 (r = 0.81, P < 0.001) T cells. In six patients there was a geometric mean decrease of greater than 2 logs in HIV levels within 2 to 6 mo after the initiation of highly active antiretroviral therapy; this was associated with a significant decrease in the percentage (but not the decay rate) of labeled cells in the rapidly proliferating pool for both CD4 (P = 0.03) and CD8 (P < 0.001) T lymphocytes. Neither plasma viral levels nor therapy had an effect on the decay rate constants or the percentage of labeled cells in the slowly proliferating pool. Monocyte production was inversely related to viral load (r = -0.56, P = 0.003) and increased with therapy (P = 0.01). These findings demonstrate that HIV does not impair CD4 T cell production but does increase CD4 and CD8 lymphocyte proliferation and death by inducing entry into a rapidly proliferating subpopulation of cells.

Key Words: AIDS • bromodeoxyuridine • CD4 T lymphocyte proliferation • CD8 T lymphocyte proliferation • highly active antiretroviral therapy

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

This article has been cited by other articles:

• Tilton, J. C., Manion, M. M., Luskin, M. R., Johnson, A. J., Patamawenu, A. A., Hallahan, C. W., Cogliano-Shutta, N. A., Mican, J. M., Davey, R. T. Jr., Kottilil, S., Lifson, J. D., Metcalf, J. A., Lempicki, R. A., Connors, M. (2008). Human Immunodeficiency Virus Viremia Induces Plasmacytoid Dendritic Cell Activation In Vivo and Diminished Alpha Interferon Production In Vitro. J. Virol. 82: 3997-4006 [Abstract] [Full Text]  
• Pandrea, I., Ribeiro, R. M., Gautam, R., Gaufin, T., Pattison, M., Barnes, M., Monjure, C., Stoulig, C., Dufour, J., Cyprian, W., Silvestri, G., Miller, M. D., Perelson, A. S., Apetrei, C. (2008). Simian Immunodeficiency Virus SIVagm Dynamics in African Green Monkeys. J. Virol. 82: 3713-3724 [Abstract] [Full Text]  
• Gordon, S. N., Dunham, R. M., Engram, J. C., Estes, J., Wang, Z., Klatt, N. R., Paiardini, M., Pandrea, I. V., Apetrei, C., Sodora, D. L., Lee, H. Y., Haase, A. T., Miller, M. D., Kaur, A., Staprans, S. I., Perelson, A. S., Feinberg, M. B., Silvestri, G. (2008). Short-Lived Infected Cells Support Virus Replication in Sooty Mangabeys Naturally Infected with Simian Immunodeficiency Virus: Implications for AIDS Pathogenesis. J. Virol. 82: 3725-3735 [Abstract] [Full Text]  
• Sedaghat, A. R., German, J., Teslovich, T. M., Cofrancesco, J. Jr., Jie, C. C., Talbot, C. C. Jr., Siliciano, R. F. (2008). Chronic CD4+ T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics. J. Virol. 82: 1870-1883 [Abstract] [Full Text]  
• Kaur, A., Di Mascio, M., Barabasz, A., Rosenzweig, M., McClure, H. M., Perelson, A. S., Ribeiro, R. M., Johnson, R. P. (2008). Dynamics of T- and B-Lymphocyte Turnover in a Natural Host of Simian Immunodeficiency Virus. J. Virol. 82: 1084-1093 [Abstract] [Full Text]  
• Biancotto, A., Iglehart, S. J., Vanpouille, C., Condack, C. E., Lisco, A., Ruecker, E., Hirsch, I., Margolis, L. B., Grivel, J.-C. (2008). HIV-1 induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivo. Blood 111: 699-704 [Abstract] [Full Text]  
• Biancotto, A., Grivel, J.-C., Iglehart, S. J., Vanpouille, C., Lisco, A., Sieg, S. F., Debernardo, R., Garate, K., Rodriguez, B., Margolis, L. B., Lederman, M. M. (2007). Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood 109: 4272-4279 [Abstract] [Full Text]  
• Asquith, B., Zhang, Y., Mosley, A. J., de Lara, C. M., Wallace, D. L., Worth, A., Kaftantzi, L., Meekings, K., Griffin, G. E., Tanaka, Y., Tough, D. F., Beverley, P. C., Taylor, G. P., Macallan, D. C., Bangham, C. R. M. (2007). In vivo T lymphocyte dynamics in humans and the impact of human T-lymphotropic virus 1 infection. Proc. Natl. Acad. Sci. USA 104: 8035-8040 [Abstract] [Full Text]  
• Koenen, P. G. F., Hofhuis, F. M., Oosterwegel, M. A., Tesselaar, K. (2007). T Cell Activation and Proliferation Characteristic for HIV-Nef Transgenic Mice Is Lymphopenia Induced. J. Immunol. 178: 5762-5768 [Abstract] [Full Text]  
• Ho, J., Moir, S., Malaspina, A., Howell, M. L., Wang, W., DiPoto, A. C., O'Shea, M. A., Roby, G. A., Kwan, R., Mican, J. M., Chun, T.-W., Fauci, A. S. (2006). Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms. Proc. Natl. Acad. Sci. USA 103: 19436-19441 [Abstract] [Full Text]  
• Tilton, J. C., Johnson, A. J., Luskin, M. R., Manion, M. M., Yang, J., Adelsberger, J. W., Lempicki, R. A., Hallahan, C. W., McLaughlin, M., Mican, J. M., Metcalf, J. A., Iyasere, C., Connors, M. (2006). Diminished Production of Monocyte Proinflammatory Cytokines during Human Immunodeficiency Virus Viremia Is Mediated by Type I Interferons. J. Virol. 80: 11486-11497 [Abstract] [Full Text]  
• Betts, M. R., Nason, M. C., West, S. M., De Rosa, S. C., Migueles, S. A., Abraham, J., Lederman, M. M., Benito, J. M., Goepfert, P. A., Connors, M., Roederer, M., Koup, R. A. (2006). HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107: 4781-4789 [Abstract] [Full Text]  
• Di Mascio, M., Sereti, I., Matthews, L. T., Natarajan, V., Adelsberger, J., Lempicki, R., Yoder, C., Jones, E., Chow, C., Metcalf, J. A., Sidorov, I. A., Dimitrov, D. S., Polis, M. A., Kovacs, J. A. (2006). Naive T-Cell Dynamics in Human Immunodeficiency Virus Type 1 Infection: Effects of Highly Active Antiretroviral Therapy Provide Insights into the Mechanisms of Naive T-Cell Depletion. J. Virol. 80: 2665-2674 [Abstract] [Full Text]  
• Davenport, M. P., Ribeiro, R. M., Perelson, A. S. (2004). Kinetics of Virus-Specific CD8+ T Cells and the Control of Human Immunodeficiency Virus Infection. J. Virol. 78: 10096-10103 [Abstract] [Full Text]  
• Moir, S., Malaspina, A., Pickeral, O. K., Donoghue, E. T., Vasquez, J., Miller, N. J., Krishnan, S. R., Planta, M. A., Turney, J. F., Justement, J. S., Kottilil, S., Dybul, M., Mican, J. M., Kovacs, C., Chun, T.-W., Birse, C. E., Fauci, A. S. (2004). Decreased Survival of B Cells of HIV-viremic Patients Mediated by Altered Expression of Receptors of the TNF Superfamily. J. Exp. Med. 200: 587-600 [Abstract] [Full Text]  
• Deeks, S. G., Kitchen, C. M. R., Liu, L., Guo, H., Gascon, R., Narvaez, A. B., Hunt, P., Martin, J. N., Kahn, J. O., Levy, J., McGrath, M. S., Hecht, F. M. (2004). Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104: 942-947 [Abstract] [Full Text]  
• Sereti, I., Anthony, K. B., Martinez-Wilson, H., Lempicki, R., Adelsberger, J., Metcalf, J. A., Hallahan, C. W., Follmann, D., Davey, R. T., Kovacs, J. A., Lane, H. C. (2004). IL-2-induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation. Blood 104: 775-780 [Abstract] [Full Text]  
• Vestereng, V. H., Kovacs, J. A. (2004). Inability of Pneumocystis organisms to incorporate bromodeoxyuridine suggests the absence of a salvage pathway for thymidine. Microbiology 150: 1179-1182 [Abstract] [Full Text]  
• Grelli, S., d'Ettorre, G., Lauria, F., Montella, F., Di Traglia, L., Lichtner, M., Vullo, V., Favalli, C., Vella, S., Macchi, B., Mastino, A. (2004). Inverse correlation between CD8+ lymphocyte apoptosis and CD4+ cell counts during potent antiretroviral therapy in HIV patients. J Antimicrob Chemother 53: 494-500 [Abstract] [Full Text]  
• Younes, S.-A., Yassine-Diab, B., Dumont, A. R., Boulassel, M.-R., Grossman, Z., Routy, J.-P., Sekaly, R.-P. (2003). HIV-1 Viremia Prevents the Establishment of Interleukin 2-producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity. J. Exp. Med. 198: 1909-1922 [Abstract] [Full Text]  
• GRELLI, S., D'ETTORE, G., LAURIA, F., MONTELLA, F., DI TRAGLIA, L., D'AGOSTINI, C., LICHTNER, M., VULLO, V., FAVALLI, C., VELLA, S., MACCHI, B., MASTINO, A. (2003). CD4+ Lymphocyte Increases in HIV Patients during Potent Antiretroviral Therapy Are Dependent on Inhibition of CD8+ Cell Apoptosis. Ann. N. Y. Acad. Sci. 1010: 560-564 [Abstract] [Full Text]  
• Monceaux, V., Fang, R. H. T., Cumont, M. C., Hurtrel, B., Estaquier, J. (2003). Distinct Cycling CD4+- and CD8+-T-Cell Profiles during the Asymptomatic Phase of Simian Immunodeficiency Virus SIVmac251 Infection in Rhesus Macaques. J. Virol. 77: 10047-10059 [Abstract] [Full Text]  
• De Boer, R. J., Mohri, H., Ho, D. D., Perelson, A. S. (2003). Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques. J. Immunol. 170: 2479-2487 [Abstract] [Full Text]  
• Chun, T.-W., Justement, J. S., Lempicki, R. A., Yang, J., Dennis, G. Jr., Hallahan, C. W., Sanford, C., Pandya, P., Liu, S., McLaughlin, M., Ehler, L. A., Moir, S., Fauci, A. S. (2003). Gene expression and viral prodution in latently infected, resting CD4+ T cells in viremic versus aviremic HIV-infected individuals. Proc. Natl. Acad. Sci. USA 100: 1908-1913 [Abstract] [Full Text]  
• Sopper, S., Nierwetberg, D., Halbach, A., Sauer, U., Scheller, C., Stahl-Hennig, C., Matz-Rensing, K., Schafer, F., Schneider, T., ter Meulen, V., Muller, J. G. (2003). Impact of simian immunodeficiency virus (SIV) infection on lymphocyte numbers and T-cell turnover in different organs of rhesus monkeys. Blood 101: 1213-1219 [Abstract] [Full Text]  
• Ribeiro, R. M., Mohri, H., Ho, D. D., Perelson, A. S. (2002). In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted?. Proc. Natl. Acad. Sci. USA 99: 15572-15577 [Abstract] [Full Text]  
• Tryniszewska, E., Nacsa, J., Lewis, M. G., Silvera, P., Montefiori, D., Venzon, D., Hel, Z., Parks, R. W., Moniuszko, M., Tartaglia, J., Smith, K. A., Franchini, G. (2002). Vaccination of Macaques with Long-Standing SIVmac251 Infection Lowers the Viral Set Point After Cessation of Antiretroviral Therapy. J. Immunol. 169: 5347-5357 [Abstract] [Full Text]  
• Gummuluru, S., KewalRamani, V. N., Emerman, M. (2002). Dendritic Cell-Mediated Viral Transfer to T Cells Is Required for Human Immunodeficiency Virus Type 1 Persistence in the Face of Rapid Cell Turnover. J. Virol. 76: 10692-10701 [Abstract] [Full Text]  
• Sousa, A. E., Carneiro, J., Meier-Schellersheim, M., Grossman, Z., Victorino, R. M. M. (2002). CD4 T Cell Depletion Is Linked Directly to Immune Activation in the Pathogenesis of HIV-1 and HIV-2 but Only Indirectly to the Viral Load. J. Immunol. 169: 3400-3406 [Abstract] [Full Text]  
• Sereti, I., Martinez-Wilson, H., Metcalf, J. A., Baseler, M. W., Hallahan, C. W., Hahn, B., Hengel, R. L., Davey, R. T., Kovacs, J. A., Lane, H. C. (2002). Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4+/CD25+ T cells. Blood 100: 2159-2167 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS