Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy

Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 × 105 cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.

[1]  J. Ware,et al.  Random-effects models for longitudinal data. , 1982, Biometrics.

[2]  R. Gallo,et al.  Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Sell,et al.  Susceptibility of normal human lymphocytes to infection with HTLV-III/LAV. , 1986, Journal of immunology.

[4]  G. Nabel,et al.  An inducible transcription factor activates expression of human immunodeficiency virus in T cells , 1987, Nature.

[5]  D. Ho,et al.  Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. , 1989, The New England journal of medicine.

[6]  J. Justement,et al.  Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Baseler,et al.  Integrated proviral human immunodeficiency virus type 1 is present in CD4+ peripheral blood lymphocytes in healthy seropositive individuals , 1989, Journal of virology.

[8]  C H Fox,et al.  The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. , 1989, Science.

[9]  A. Collier,et al.  Plasma viremia in human immunodeficiency virus infection. , 1989, The New England journal of medicine.

[10]  Jerome A. Zack,et al.  HIV-1 entry into quiescent primary lymphocytes: Molecular analysis reveals a labile, latent viral structure , 1990, Cell.

[11]  D. Baltimore,et al.  Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: A molecular model for latency , 1990, Cell.

[12]  A. Fauci,et al.  Lymphoid organs function as major reservoirs for human immunodeficiency virus. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Ho,et al.  Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. , 1991, The New England journal of medicine.

[14]  M P Dempsey,et al.  Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. , 1991, Science.

[15]  B. Cullen,et al.  Molecular basis of latency in pathogenic human viruses. , 1991, Science.

[16]  P. Volberding,et al.  HIV-1 protease inhibitors , 1992 .

[17]  S. J. Clark,et al.  High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. , 1993, Science.

[18]  Anthony S. Fauci,et al.  HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease , 1993, Nature.

[19]  L. McQuay,et al.  Dilution assay statistics , 1994, Journal of clinical microbiology.

[20]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[21]  Robert F. Siliciano,et al.  In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency , 1995, Nature Medicine.

[22]  Martin A. Nowak,et al.  Viral dynamics in human immunodeficiency virus type 1 infection , 1995, Nature.

[23]  A. McLean,et al.  In vivo estimates of division and death rates of human T lymphocytes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  A. Perelson,et al.  HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time , 1996, Science.

[25]  John W. Mellors,et al.  Prognosis in HIV-1 Infection Predicted by the Quantity of Virus in Plasma , 1996, Science.

[26]  J. Bartlett,et al.  Medical Management of HIV Infection , 1996 .

[27]  K. Smith,et al.  Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R Brookmeyer,et al.  Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. , 1997, Science.

[29]  D. Richman,et al.  Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. , 1998, JAMA.

[31]  E A Emini,et al.  Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. , 1997, The New England journal of medicine.

[32]  Correlation of virus load in plasma and lymph node tissue in human immunodeficiency virus infection. INCAS Study Group. Italy, Netherlands, Canada, Australia, and (United) States. , 1997, The Journal of infectious diseases.

[33]  M A Nowak,et al.  Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Siliciano,et al.  Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection , 1997, Nature.

[35]  M A Fischl,et al.  A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. , 1997, The New England journal of medicine.

[36]  E. Rosenberg,et al.  Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. , 1997, Science.

[37]  Alan S. Perelson,et al.  Decay characteristics of HIV-1-infected compartments during combination therapy , 1997, Nature.

[38]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[39]  C. Flexner HIV-protease inhibitors. , 1998, The New England journal of medicine.

[40]  D. Richman,et al.  Human Immunodeficiency Virus Replication and Genotypic Resistance in Blood and Lymph Nodes after a Year of Potent Antiretroviral Therapy , 1998, Journal of Virology.

[41]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[42]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. , 1997, JAMA.

[43]  M. Dybul,et al.  Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy , 1999, Nature Medicine.

[44]  J. Metcalf,et al.  HIV-1 replication in patients with undetectable plasma virus receiving HAART , 1999, The Lancet.