title: Reconciling Longitudinal Naive T-Cell and TREC Dynamics during HIV-1 Infection.
abstract: Naive T cells in untreated HIV-1 infected individuals have a reduced T-cell receptor excision circle (TREC) content. Previous mathematical models have suggested that this is due to increased naive T-cell division. It remains unclear, however, how reduced naive TREC contents can be reconciled with a gradual loss of naive T cells in HIV-1 infection. We performed longitudinal analyses in humans before and after HIV-1 seroconversion, and used a mathematical model to investigate which processes could explain the observed changes in naive T-cell numbers and TRECs during untreated HIV-1 disease progression. Both CD4+ and CD8+ naive T-cell TREC contents declined biphasically, with a rapid loss during the first year and a much slower loss during the chronic phase of infection. While naive CD8+ T-cell numbers hardly changed during follow-up, naive CD4+ T-cell counts continually declined. We show that a fine balance between increased T-cell division and loss in the peripheral naive T-cell pool can explain the observed short- and long-term changes in TRECs and naive T-cell numbers, especially if T-cell turnover during the acute phase is more increased than during the chronic phase of infection. Loss of thymic output, on the other hand, does not help to explain the biphasic loss of TRECs in HIV infection. The observed longitudinal changes in TRECs and naive T-cell numbers in HIV-infected individuals are most likely explained by a tight balance between increased T-cell division and death, suggesting that these changes are intrinsically linked in HIV infection.
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|Theoretical Biology & Bioinformatics, Department of Biology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Julia
authors.initials: J
authors.lastname: Drylewicz
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: Vrisekoop
authors.affiliation: Theoretical Biology & Bioinformatics, Department of Biology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Tendai
authors.initials: T
authors.lastname: Mugwagwa
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Anne Bregje
authors.initials: AB
authors.lastname: de Boer
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sigrid A
authors.initials: SA
authors.lastname: Otto
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mette D
authors.initials: MD
authors.lastname: Hazenberg
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kiki
authors.initials: K
authors.lastname: Tesselaar
authors.affiliation: Theoretical Biology & Bioinformatics, Department of Biology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: de Boer
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: José A M
authors.initials: JA
authors.lastname: Borghans
mesh_terms: D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008137:Longitudinal Studies; D013601:T-Lymphocytes / Q000276:immunology*