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Science 14 November 1997:
Vol. 278. no. 5341, pp. 1295 - 1300
DOI: 10.1126/science.278.5341.1295

Reports

Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy

Diana Finzi, Monika Hermankova, Theodore Pierson, Lucy M. Carruth, Christopher Buck, Richard E. Chaisson, Thomas C. Quinn, Karen Chadwick, Joseph Margolick, Ronald Brookmeyer, Joel Gallant, Martin Markowitz, David D. Ho, Douglas D. Richman, Robert F. Siliciano *

The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 106 cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.

D. Finzi, M. Hermankova, T. Pierson, L. M. Carruth, C. Buck, R. E. Chaisson, T. C. Quinn, J. Gallant, R. F. Siliciano, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
K. Chadwick and J. Margolick, Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205, USA.
R. Brookmeyer, Department of Biostatistics, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205, USA.
M. Markowitz and D. D. Ho, Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA.
D. D. Richman, Departments of Medicine and Pathology, University of California San Diego, La Jolla CA 92093, USA.
*   To whom correspondence should be addressed.


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Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity.
J. J. Lum, D. J. Schnepple, Z. Nie, J. Sanchez-Dardon, G. L. Mbisa, J. Mihowich, N. Hawley, S. Narayan, J. E. Kim, D. H. Lynch, et al. (2004)
J. Virol. 78, 6033-6042
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CpG Oligodeoxynucleotides Activate HIV Replication in Latently Infected Human T Cells.
C. Scheller, A. Ullrich, K. McPherson, B. Hefele, J. Knoferle, S. Lamla, A. R. M. Olbrich, H. Stocker, K. Arasteh, V. t. Meulen, et al. (2004)
J. Biol. Chem. 279, 21897-21902
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Where Does HIV Live?.
J. Stebbing, B. Gazzard, and D. C. Douek (2004)
N. Engl. J. Med. 350, 1872-1880
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P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy.
S. U. C. Sankatsing, J. H. Beijnen, A. H. Schinkel, J. M. A. Lange, and J. M. Prins (2004)
Antimicrob. Agents Chemother. 48, 1073-1081
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Retinoid-Dependent Restriction of Human Immunodeficiency Virus Type 1 Replication in Monocytes/Macrophages.
T. M. Hanley, H. L. B. Kiefer, A. C. Schnitzler, J. E. Marcello, and G. A. Viglianti (2004)
J. Virol. 78, 2819-2830
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HIV Drug Resistance.
F. Clavel and A. J. Hance (2004)
N. Engl. J. Med. 350, 1023-1035
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Highly Uneven Distribution of Tenofovir-Selected Simian Immunodeficiency Virus in Different Anatomical Sites of Rhesus Macaques.
M. Magierowska, F. Bernardin, S. Garg, S. Staprans, M. D. Miller, K. K. A. Van Rompay, and E. L. Delwart (2004)
J. Virol. 78, 2434-2444
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Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1.
H. Zhang, Y. Zhou, C. Alcock, T. Kiefer, D. Monie, J. Siliciano, Q. Li, P. Pham, J. Cofrancesco, D. Persaud, et al. (2004)
J. Virol. 78, 1718-1729
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Antibody-Dependent Cellular Cytotoxicity via Humoral Immune Epitope of Nef Protein Expressed on Cell Surface.
T. Yamada, N. Watanabe, T. Nakamura, and A. Iwamoto (2004)
J. Immunol. 172, 2401-2406
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Co-existence of recent and ancestral nucleotide sequences in viral quasispecies of human immunodeficiency virus type 1 patients.
G. Bello, C. Casado, S. Garcia, C. Rodriguez, J. del Romero, and C. Lopez-Galindez (2004)
J. Gen. Virol. 85, 399-407
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Continued Production of Drug-Sensitive Human Immunodeficiency Virus Type 1 in Children on Combination Antiretroviral Therapy Who Have Undetectable Viral Loads.
D. Persaud, G. K. Siberry, A. Ahonkhai, J. Kajdas, D. Monie, N. Hutton, D. C. Watson, T. C. Quinn, S. C. Ray, and R. F. Siliciano (2004)
J. Virol. 78, 968-979
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Different Sensitivity to Apoptosis in Cells of Monocytic or Lymphocytic Origin Chronically Infected with Human Immunodeficiency Virus Type-1.
M. Pinti, P. Biswas, L. Troiano, M. Nasi, R. Ferraresi, C. Mussini, J. Vecchiet, R. Esposito, R. Paganelli, and A. Cossarizza (2003)
Experimental Biology and Medicine 228, 1346-1354
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Inferring Evolutionary Rates Using Serially Sampled Sequences from Several Populations.
A. G. Rodrigo, M. Goode, R. Forsberg, H. A. Ross, and A. Drummond (2003)
Mol. Biol. Evol. 20, 2010-2018
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The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection.
S. Crowe, T. Zhu, and W. A. Muller (2003)
J. Leukoc. Biol. 74, 635-641
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Identification of T cell-signaling pathways that stimulate latent HIV in primary cells.
D. G. Brooks, P. A. Arlen, L. Gao, C. M. R. Kitchen, and J. A. Zack (2003)
PNAS 100, 12955-12960
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Productive Infection Maintains a Dynamic Steady State of Residual Viremia in Human Immunodeficiency Virus Type 1-Infected Persons Treated with Suppressive Antiretroviral Therapy for Five Years.
D. V. Havlir, M. C. Strain, M. Clerici, C. Ignacio, D. Trabattoni, P. Ferrante, and J. K. Wong (2003)
J. Virol. 77, 11212-11219
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New Real-Time Reverse Transcriptase-Initiated PCR Assay with Single-Copy Sensitivity for Human Immunodeficiency Virus Type 1 RNA in Plasma.
S. Palmer, A. P. Wiegand, F. Maldarelli, H. Bazmi, J. M. Mican, M. Polis, R. L. Dewar, A. Planta, S. Liu, J. A. Metcalf, et al. (2003)
J. Clin. Microbiol. 41, 4531-4536
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Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection: A Randomized Trial.
K. Squires, A. L. Pozniak, G. Pierone Jr., C. R. Steinhart, D. Berger, N. C. Bellos, S. L. Becker, M. Wulfsohn, M. D. Miller, J. J. Toole, et al. (2003)
Ann Intern Med 139, 313-320
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Transcriptional Profiles of Latent Human Immunodeficiency Virus in Infected Individuals: Effects of Tat on the Host and Reservoir.
X. Lin, D. Irwin, S. Kanazawa, L. Huang, J. Romeo, T. S. B. Yen, and B. M. Peterlin (2003)
J. Virol. 77, 8227-8236
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Analysis of Human Immunodeficiency Virus Type 1 Gene Expression in Latently Infected Resting CD4+ T Lymphocytes In Vivo.
M. Hermankova, J. D. Siliciano, Y. Zhou, D. Monie, K. Chadwick, J. B. Margolick, T. C. Quinn, and R. F. Siliciano (2003)
J. Virol. 77, 7383-7392
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Nuclear Export of Vpr Is Required for Efficient Replication of Human Immunodeficiency Virus Type 1 in Tissue Macrophages.
M. P. Sherman, C. M. C. de Noronha, L. A. Eckstein, J. Hataye, P. Mundt, S. A. F. Williams, J. A. Neidleman, M. A. Goldsmith, and W. C. Greene (2003)
J. Virol. 77, 7582-7589
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Persistence of Extraordinarily Low Levels of Genetically Homogeneous Human Immunodeficiency Virus Type 1 in Exposed Seronegative Individuals.
T. Zhu, L. Corey, Y. Hwangbo, J. M. Lee, G. H. Learn, J. I. Mullins, and M. J. McElrath (2003)
J. Virol. 77, 6108-6116
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A Prospective Trial of Structured Treatment Interruptions in Human Immunodeficiency Virus Infection.
C. Fagard, A. Oxenius, H. Gunthard, F. Garcia, M. Le Braz, G. Mestre, M. Battegay, H. Furrer, P. Vernazza, E. Bernasconi, et al. (2003)
Arch Intern Med 163, 1220-1226
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Multiple Viral Genetic Analyses Detect Low-Level Human Immunodeficiency Virus Type 1 Replication during Effective Highly Active Antiretroviral Therapy.
L. M. Frenkel, Y. Wang, G. H. Learn, J. L. McKernan, G. M. Ellis, K. M. Mohan, S. E. Holte, S. M. De Vange, D. M. Pawluk, A. J. Melvin, et al. (2003)
J. Virol. 77, 5721-5730
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Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity.
D. A. Price, G. Scullard, A. Oxenius, R. Braganza, S. A. Beddows, S. Kazmi, J. R. Clarke, G. E. Johnson, J. N. Weber, and R. E. Phillips (2003)
J. Virol. 77, 6041-6049
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Susceptibilities of Simian Immunodeficiency Virus to Protease Inhibitors.
A. C. Giuffre, J. Higgins, R. W. Buckheit Jr., and T. W. North (2003)
Antimicrob. Agents Chemother. 47, 1756-1759
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Evolutionary Indicators of Human Immunodeficiency Virus Type 1 Reservoirs and Compartments.
D. C. Nickle, M. A. Jensen, D. Shriner, S. J. Brodie, L. M. Frenkel, J. E. Mittler, and J. I. Mullins (2003)
J. Virol. 77, 5540-5546
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Resting CD4+ T Lymphocytes but Not Thymocytes Provide a Latent Viral Reservoir in a Simian Immunodeficiency Virus-Macaca nemestrina Model of Human Immunodeficiency Virus Type 1-Infected Patients on Highly Active Antiretroviral Therapy.
A. Shen, M. C. Zink, J. L. Mankowski, K. Chadwick, J. B. Margolick, L. M. Carruth, M. Li, J. E. Clements, and R. F. Siliciano (2003)
J. Virol. 77, 4938-4949
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Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence.
M. C. Strain, H. F. Gunthard, D. V. Havlir, C. C. Ignacio, D. M. Smith, A. J. Leigh-Brown, T. R. Macaranas, R. Y. Lam, O. A. Daly, M. Fischer, et al. (2003)
PNAS 100, 4819-4824
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Transcriptional Suppression of In Vitro-Integrated Human Immunodeficiency Virus Type 1 Does Not Correlate with Proviral DNA Methylation.
M. Pion, A. Jordan, A. Biancotto, F. Dequiedt, F. Gondois-Rey, S. Rondeau, R. Vigne, J. Hejnar, E. Verdin, and I. Hirsch (2003)
J. Virol. 77, 4025-4032
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New Anti-Human Immunodeficiency Virus Type 1 6-Aminoquinolones: Mechanism of Action.
C. Parolin, B. Gatto, C. Del Vecchio, T. Pecere, E. Tramontano, V. Cecchetti, A. Fravolini, S. Masiero, M. Palumbo, and G. Palu (2003)
Antimicrob. Agents Chemother. 47, 889-896
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Genetic Characterization of Rebounding Human Immunodeficiency Virus Type 1 in Plasma during Multiple Interruptions of Highly Active Antiretroviral Therapy.
M. Dybul, M. Daucher, M. A. Jensen, C. W. Hallahan, T.-W. Chun, M. Belson, B. Hidalgo, D. C. Nickle, C. Yoder, J. A. Metcalf, et al. (2003)
J. Virol. 77, 3229-3237
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