Normal Telomere Lengths in Naive and Memory CD4+ T Cells in HIV Type 1 Infection: A Mathematical Interpretation

Wolthers, Katja C.; Noest, André J.; Otto, Sigrid A.; Miedema, Frank; Boer, Rob J. de

doi:10.1089/088922299310340

Cited by 28 publications

(22 citation statements)

References 50 publications

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“…In this data, the increase in average cellular turnover rates caused by SIV infection is typically Ͻ2-fold. This level of increase in cellular turnover is in good agreement with telomere data showing little effect of HIV infection on the average telomere length in naive and memory CD4 ϩ T cells (17,48), and with TCR rearrangement excision circle data showing a decrease in the TCR rearrangement excision circles per naive T cell in response to a small increase in the division rate (49).…”

Section: Discussionsupporting

confidence: 89%

Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques

Boer

Mohri

et al. 2003

The Journal of Immunology

110

134

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We determined average cellular turnover rates by fitting mathematical models to 5-bromo-2′-deoxyuridine measurements in SIV-infected and uninfected rhesus macaques. The daily turnover rates of CD4+ T cells, CD4− T cells, CD20+ B cells, and CD16+ NK cells in normal uninfected rhesus macaques were 1, 1, 2, and 2%, respectively. Daily turnover rates of CD45RA− memory T cells were 1%, and those of CD45RA+ naive T cells were 0.5% for CD4+ T cells and ∼1% for CD4−CD45RA+ T cells. In SIV-infected monkeys with high viral loads, the turnover rates of T cells were increased ∼2-fold, and that of memory T cells ∼3-fold. The turnover of CD4+CD45RA+ naive T cells was increased 2-fold, whereas that of CD4−CD45RA+ naive T cells was marginally increased. B cells and NK cells also had increased turnover in SIV-infected macaques, averaging 3 and 2.5% per day, respectively. For all cell types studied here the daily turnover rate increased with the decrease of the CD4 count that accompanied SIV infection. As a consequence, the turnover rates of CD4+ T cells, CD4− T cells, B cells, and NK cells within each monkey are strongly correlated. This suggests that the cellular turnover of different lymphocyte populations is governed by a similar process which one could summarize as “generalized immune activation.” Because the viral load and the CD4 T cell count are negatively correlated we cannot determine which of the two plays the most important role in this generalized immune activation.

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Section: Discussionsupporting

confidence: 89%

Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques

Boer

Mohri

et al. 2003

The Journal of Immunology

110

134

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“…First, by determining the fraction of dividing cells through expression of the nuclear antigen Ki67 (12), it was shown that T-cell proliferation rate is increased maximally twofold to threefold in the CD4 + population, and sixfold to sevenfold in the CD8 population (13-16). This limited increase in the division rate is consistent with results of studies that measured the replicative history of T cells by the average telomere lengths (17,18). The second technique, using deuterated glucose to label DNA in vivo, showed that the turnover of CD4 + and CD8 + T cells in HIV-infected patients is about three times higher than that of uninfected individuals (19).…”

supporting

confidence: 75%

The Dominant Source of CD4+ and CD8+ T-Cell Activation in HIV Infection Is Antigenic Stimulation

Stuart¹,

Hazebergh²,

Hamann³

et al. 2000

Journal of Acquired Immune Deficiency Syndromes

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Summary:To distinguish between antigenic stimulation and CD4 + T-cell homeostasis as the cause of T-cell hyperactivation in HIV infection, we studied T-cell activation in 47 patients before and during highly active antiretroviral therapy (HAART). We show that expression of human leukocyte antigen (HLA)-DR, CD38, and Ki67 on T cells decreased during HAART but remained elevated over normal values until week 48 of therapy. We confirm previous reports that T-cell activation correlates positively with plasma HIV RNA levels (suggesting antigenic stimulation), and negatively with CD4 count (suggesting CD4 + T-cell homeostasis). However, these correlations may be spurious, because misleading, due to the well-established negative correlation between CD4 count and plasma HIV RNA levels. To resolve this conflict, we computed partial correlation coefficients. Correcting for CD4 counts, we show that plasma HIV RNA levels contributed to T-cell hyperactivation. Correcting for plasma HIV RNA levels, we show that CD4 + T-cell depletion contributed to T-cell activation. Correcting for both, activation of CD4 + and CD8 + T cells remained positively correlated. Because this suggests that CD4 + and CD8 + T-cell activation is caused by a common additional factor, we conclude that antigenic stimulation by HIV or other (opportunistic) infections is the most parsimonious explanation for T-cell activation in HIV infection. Persistence of HIV antigens may explain why T-cell activation fails to revert to levels found in healthy individuals after 48 weeks of therapy. Key Words: ActivationProliferation-T lymphocytes-CD4-CD8-Antiretroviral therapy.T lymphocytes of HIV-infected people have increased expression of activation markers human leukocyte antigen (HLA)-DR and CD38 (1-11) and increased proliferation rates. The latter has been demonstrated using two different techniques. First, by determining the fraction of dividing cells through expression of the nuclear antigen Ki67 (12), it was shown that T-cell proliferation rate is increased maximally twofold to threefold in the CD4 + population, and sixfold to sevenfold in the CD8 population (13-16). This limited increase in the division rate is consistent with results of studies that measured the replicative history of T cells by the average telomere lengths (17,18). The second technique, using deuterated glucose to label DNA in vivo, showed that the turnover of CD4 + and CD8 + T cells in HIV-infected patients is about three times higher than that of uninfected individuals (19). Increased turnover of CD4 + and CD8 + T lymphocytes has also been observed in macaques infected with simian immunodeficiency virus using BrdU to label DNA in vivo (20).Two models have been proposed to explain the hyperactivation and increased proliferation of T cells in HIV-1 infection. One model contends that T-lymphocyte acti-

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“…As we have discussed, new experimental evidence on T cell production numbers in normal controls and HIV-infected patients suggests that CD4+ T cell production is about two-to threefold increased with HIV-1 infection and is on the order of 109 cells per day ( Table I). Studies that provided a mathematical interpretation of telomere length dynamics in CD45RA+ and CD45R0+ CD4+ cells demonstrated that telomere shortening rates comparable to uninfected controls are compatible with a small increase in production of CD4+ T cells (Wolthers et al, 1996(Wolthers et al, , 1998. Therefore, the data suggest that there is a modest increase in the amount of proliferation of T cells in HIV-1-infected individuals.…”

Section: What Is the Cause Of Cd4+ T Cell Depletion In Hiv-1 Infementioning

confidence: 80%

T Cell Dynamics in HIV-1 Infection

Clark

Boer

Wolthers

et al. 1999

Advances in Immunology

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Normal Telomere Lengths in Naive and Memory CD4+ T Cells in HIV Type 1 Infection: A Mathematical Interpretation

Abstract: To study CD4

Cited by 28 publications

References 50 publications

Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques

Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques

The Dominant Source of CD4+ and CD8+ T-Cell Activation in HIV Infection Is Antigenic Stimulation

T Cell Dynamics in HIV-1 Infection

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