In vivo T lymphocyte dynamics in humans and the impact of human T-lymphotropic virus 1 infection

Human T-lymphotropic virus type 1 (HTLV-1) is a persistent CD4+ T-lymphotropic retrovirus. Most HTLV-1-infected individuals remain asymptomatic, but a proportion develop adult T cell leukemia or inflammatory disease. It is not fully understood how HTLV-1 persists despite a strong immune response or what determines the risk of HTLV-1-associated diseases. Until recently, it has been difficult to quantify lymphocyte kinetics in humans in vivo. Here, we used deuterated glucose labeling to quantify in vivo lymphocyte dynamics in HTLV-1-infected individuals. We then used these results to address four questions. (i) What is the impact of HTLV-1 infection on lymphocyte dynamics? (ii) How does HTLV-1 persist? (iii) What is the extent of HTLV-1 expression in vivo? (iv) What features of lymphocyte kinetics are associated with HTLV-1-associated myelopathy/tropical spastic paraparesis? We found that CD4+CD45RO+ and CD8+CD45RO+ T lymphocyte proliferation was elevated in HTLV-1-infected subjects compared with controls, with an extra 1012 lymphocytes produced per year in an HTLV-1-infected subject. The in vivo proliferation rate of CD4+CD45RO+ cells also correlated with ex vivo viral expression. Finally, the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with significantly increased CD4+CD45RO+ cell proliferation. We suggest that there is persistent viral gene expression in vivo, which is necessary for the maintenance of the proviral load and determines HTLV-1-associated myelopathy/tropical spastic paraparesis risk.

[1]  Yan Zhang,et al.  Rapid turnover of T cells in acute infectious mononucleosis , 2003, European journal of immunology.

[2]  M. Biard-Piechaczyk,et al.  The Complementary Strand of the Human T-Cell Leukemia Virus Type 1 RNA Genome Encodes a bZIP Transcription Factor That Down-Regulates Viral Transcription , 2002, Journal of Virology.

[3]  S. Wain-Hobson,et al.  Proliferation of HTLV-1 infected circulating cells in vivo in all asymptomatic carriers and patients with TSP/HAM. , 1996, Oncogene.

[4]  P Rudge,et al.  In vivo cellular tropism of human T-cell leukemia virus type 1 , 1990, Journal of virology.

[5]  M. Yoshida,et al.  Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. , 2001, Annual review of immunology.

[6]  A. McLean,et al.  Quantification of the virus-host interaction in human T lymphotropic virus I infection , 2005, Retrovirology.

[7]  M. Nowak,et al.  HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Becca Asquith,et al.  A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load. , 2005, The Journal of general virology.

[9]  D. Tough,et al.  Direct Measurement of T Cell Subset Kinetics In Vivo in Elderly Men and Women1 , 2004, The Journal of Immunology.

[10]  D. Tough,et al.  Measurement and modeling of human T cell kinetics , 2003 .

[11]  M. Matsuoka,et al.  Genetic and epigenetic inactivation of tax gene in adult T‐cell leukemia cells , 2004, International journal of cancer.

[12]  A. Ureta-Vidal,et al.  Evidence for the Chronic in Vivo Production of Human T Cell Leukemia Virus Type I Rof and Tof Proteins from Cytotoxic T Lymphocytes Directed against Viral Peptides , 2000, The Journal of experimental medicine.

[13]  Alan S. Perelson,et al.  Increased Turnover of T Lymphocytes in HIV-1 Infection and Its Reduction by Antiretroviral Therapy , 2001, The Journal of experimental medicine.

[14]  J. Weber,et al.  Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognize multiple epitopes simultaneously , 1994, Journal of virology.

[15]  J. Weber,et al.  Abundant tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes. , 2000, Blood.

[16]  T. Misteli,et al.  HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication , 2004, Nature Medicine.

[17]  L. Ratner,et al.  Selective ablation of human T-cell lymphotropic virus type 1 p12I reduces viral infectivity in vivo. , 1998, Blood.

[18]  M. Yoshida,et al.  Two cis-acting elements responsible for posttranscriptional trans-regulation of gene expression of human T-cell leukemia virus type I. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Becca Asquith,et al.  Lymphocyte kinetics: the interpretation of labelling data. , 2002, Trends in immunology.

[20]  Michael L. Gatza,et al.  Cellular Transformation by the HTLV-I Tax Protein, a Jack-of-All-Trades , 2003, Oncogene.

[21]  J. Hay,et al.  The Relationship of Blood Lymphocytes to the Recirculating Lymphocyte Pool , 1998 .

[22]  D. Tough,et al.  B-cell kinetics in humans: rapid turnover of peripheral blood memory cells. , 2005, Blood.

[23]  Y. Koyanagi,et al.  Effect of human serum anti‐htlv antibodies on viral antigen induction in In vitro cultured peripheral lymphocytes from adult T‐CELL leukemia patients and healthy virus carriers , 1985, International journal of cancer.

[24]  W. Leonard,et al.  HTLV-1 p12(I) protein enhances STAT5 activation and decreases the interleukin-2 requirement for proliferation of primary human peripheral blood mononuclear cells. , 2001, Blood.

[25]  D. McFarlin,et al.  Isolation of an HTLV-1-like retrovirus from patients with tropical spastic paraparesis , 1988, Nature.

[26]  L. Mansky.  In Vivo Analysis of Human T-Cell Leukemia Virus Type 1 Reverse Transcription Accuracy , 2000, Journal of Virology.

[27]  L. Ratner,et al.  Human T-Cell Lymphotropic Virus Type 1 Open Reading Frame II-Encoded p30II Is Required for In Vivo Replication: Evidence of In Vivo Reversion , 2004, Journal of Virology.

[28]  M. Hellerstein,et al.  Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro, in animals, and in humans. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  L. Wedderburn,et al.  Clonal Expansions in Acute EBV Infection Are Detectable in the CD8 and not the CD4 Subset and Persist with a Variable CD45 Phenotype1 , 2000, The Journal of Immunology.

[30]  A. Lloyd,et al.  The Influence of HLA Class I Alleles and Heterozygosity on the Outcome of Human T Cell Lymphotropic Virus Type I Infection1 , 2000, The Journal of Immunology.

[31]  A. Fauci,et al.  Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease , 1990, Nature.

[32]  F. Martínez-Murillo,et al.  The Role of CTLs in Persistent Viral Infection: Cytolytic Gene Expression in CD8+ Lymphocytes Distinguishes between Individuals with a High or Low Proviral Load of Human T Cell Lymphotropic Virus Type 1 , 2004, The Journal of Immunology.

[33]  L. Ratner,et al.  Human T-Lymphotropic Virus Type 1 Open Reading Frame I p12I Is Required for Efficient Viral Infectivity in Primary Lymphocytes , 2000, Journal of Virology.

[34]  S. Wain-Hobson,et al.  Persistent oligoclonal expansion of human T-cell leukemia virus type 1-infected circulating cells in patients with Tropical spastic paraparesis/HTLV-1 associated myelopathy , 1998, Oncogene.

[35]  Richard A. Lempicki,et al.  Identification of Dynamically Distinct Subpopulations of T Lymphocytes That Are Differentially Affected by HIV , 2001, The Journal of experimental medicine.

[36]  S. Marshall,et al.  Human T cell lymphotropic virus (HTLV) type-1-specific CD8+ T cells: frequency and immunodominance hierarchy. , 2004, The Journal of infectious diseases.

[37]  L. Ratner,et al.  Functional Role of pX Open Reading Frame II of Human T-Lymphotropic Virus Type 1 in Maintenance of Viral Loads In Vivo , 2000, Journal of Virology.

[38]  Maini,et al.  A comparison of two techniques for the molecular tracking of specific T‐cell responses; CD4+ human T‐cell clones persist in a stable hierarchy but at a lower frequency than clones in the CD8+ population , 1998, Immunology.

[39]  S. Jacobson,et al.  Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-1-associated myelopathy (HAM/TSP). , 2002, Blood.

[40]  Becca Asquith,et al.  Quantifying lymphocyte kinetics in vivo using carboxyfluorescein diacetate succinimidyl ester , 2006, Proceedings of the Royal Society B: Biological Sciences.

[41]  O. J. Semmes,et al.  PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo. , 2006, Blood.

[42]  T. Gojobori,et al.  Molecular evolution of human T-cell leukemia virus , 1990, Journal of Molecular Evolution.