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Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy.

Mohri H, Perelson AS, Tung K, Ribeiro RM, Ramratnam B, Markowitz M, Kost R, Hurley A, Weinberger L, Cesar D, Hellerstein MK, Ho DD - J. Exp. Med. (2001)

Bottom Line: In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls.Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy.Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

View Article: PubMed Central - PubMed

Affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA.

ABSTRACT
The mechanism of CD4(+) T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1-infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8(+) T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4(+) and CD8(+) cell populations were substantially reduced by 5-11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

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Related in: MedlinePlus

A newly developed mathematical model to track labeled and unlabeled strands of DNA before, during and after D-glucose administration. A full explanation is given in Materials and Methods.
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fig1: A newly developed mathematical model to track labeled and unlabeled strands of DNA before, during and after D-glucose administration. A full explanation is given in Materials and Methods.

Mentions: Before D-glucose administration, we assume that the number of both CD4+ and CD8+ T cells, T, is determined by equation 1 in Fig. 1 , where s is the rate of T cell entry into the proliferative compartment, p is the proliferation rate per cell, and d is the death rate per cell. During D-glucose administration when cell proliferation occurs, an unlabeled DNA strand, U, is copied and a labeled strand, L, is created while U is preserved. Thus, U→U + L. Similarly, when a labeled strand is copied, L→L + L. These kinetics are described by equations 2 a and b, where the initial amounts of unlabeled and labeled DNA are U(0) and L(0), respectively, p and d are as in equation 1, and the source s now has two components: an unlabled part sU and a labeled one sL, such that s = sU+ sL. If we assume that the system is at steady state, the amount of DNA in the system will not change over time, and for the first labeling the fraction of labeled DNA is given by fL(t) = L(t)/[U(0)+L(0)]. For the first labeling, L(0) = 0, since initially there is no labeled DNA. From equations 2 a and b we obtain for the fraction of labeled DNA during D-glucose administration, fL(t)=1−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{\overline{{\mathit{s}}}_{{\mathit{U}}}}/{{\mathit{d}}}\end{equation*}\end{document}1−e−dt, where we have defined \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}u as sU/U(0); thus, the source is measured relative to the total amount of DNA in the compartment. After D-glucose administration, U→U + U and L→L + U, leading to equations 3 a and b, where we use sU′ and sL′ for the source terms. The primes indicate that the sources after D-glucose administration may have changed, e.g., more of the source may be labeled, but the total source is still s = sU′ + sL′. From the solution of equation 3 a, we calculate the fraction of labeled DNA by fLt=fLte−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{\overline{{\mathit{s}}}_{{\mathit{L}}}^{\prime}}/{{\mathit{d}}}\end{equation*}\end{document}e−dt−te+\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{\overline{{\mathit{s}}}_{{\mathit{L}}}^{\prime}}/{{\mathit{d}}}\end{equation*}\end{document}, where \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L′=\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{ \left \left(\overline{{\mathit{s}}}_{{\mathit{L}}}^{\prime}\right) \right }/{{\mathit{U}} \left \left(0\right) \right }\end{equation*}\end{document}. In this equation, fL(te) represents the fraction of labeled DNA at the time, te, that D-glucose infusion ends. While the proliferation rate does not appear in the equations for fL(t), it can be estimated using the steady state condition p = d − s/T or in the case of DNA, p = d − (sU+ sL)/U(0); thus, p>d−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}U. Because we expect \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L<\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L′, p<d−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}U+\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L′, these two estimates of p turn out to be close to each other and in Table I we report their mean. The initial slope of the labeling curve is d−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}U, which to a good approximation is p. When D-glucose is administered for a second or third time to the same patient, the expressions given above for fL(t) are modified to account for any existing labeled DNA at the start of the infusion. Also, when the measurements of total CD4+ and CD8+ T cells indicate a significant change in the population, we relax the assumption of steady state. In this case, we used the solution of equation 1 to determine the total amount of DNA at time t to be used in the calculation of the fraction of labeled DNA. Finally, because most T cells are in tissues, we assumed that after labeling there would be a delay τ before labeled DNA first appeared in blood. Further, when D-glucose administration ended at time te, we also assumed labeled DNA would continue to accumulate in the blood until time te + τ. Thus, on the right hand side of the equations given above for fL(t), t should be replaced by t − τ, and for 0< t < τ, fL(t) = 0. To model monocyte kinetics, we assume no proliferation occurs in the periphery, i.e., p = 0 in equations 1–3, and d is interpreted as a rate of monocyte export out of blood.


Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy.

Mohri H, Perelson AS, Tung K, Ribeiro RM, Ramratnam B, Markowitz M, Kost R, Hurley A, Weinberger L, Cesar D, Hellerstein MK, Ho DD - J. Exp. Med. (2001)

A newly developed mathematical model to track labeled and unlabeled strands of DNA before, during and after D-glucose administration. A full explanation is given in Materials and Methods.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195973&req=5

fig1: A newly developed mathematical model to track labeled and unlabeled strands of DNA before, during and after D-glucose administration. A full explanation is given in Materials and Methods.
Mentions: Before D-glucose administration, we assume that the number of both CD4+ and CD8+ T cells, T, is determined by equation 1 in Fig. 1 , where s is the rate of T cell entry into the proliferative compartment, p is the proliferation rate per cell, and d is the death rate per cell. During D-glucose administration when cell proliferation occurs, an unlabeled DNA strand, U, is copied and a labeled strand, L, is created while U is preserved. Thus, U→U + L. Similarly, when a labeled strand is copied, L→L + L. These kinetics are described by equations 2 a and b, where the initial amounts of unlabeled and labeled DNA are U(0) and L(0), respectively, p and d are as in equation 1, and the source s now has two components: an unlabled part sU and a labeled one sL, such that s = sU+ sL. If we assume that the system is at steady state, the amount of DNA in the system will not change over time, and for the first labeling the fraction of labeled DNA is given by fL(t) = L(t)/[U(0)+L(0)]. For the first labeling, L(0) = 0, since initially there is no labeled DNA. From equations 2 a and b we obtain for the fraction of labeled DNA during D-glucose administration, fL(t)=1−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{\overline{{\mathit{s}}}_{{\mathit{U}}}}/{{\mathit{d}}}\end{equation*}\end{document}1−e−dt, where we have defined \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}u as sU/U(0); thus, the source is measured relative to the total amount of DNA in the compartment. After D-glucose administration, U→U + U and L→L + U, leading to equations 3 a and b, where we use sU′ and sL′ for the source terms. The primes indicate that the sources after D-glucose administration may have changed, e.g., more of the source may be labeled, but the total source is still s = sU′ + sL′. From the solution of equation 3 a, we calculate the fraction of labeled DNA by fLt=fLte−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{\overline{{\mathit{s}}}_{{\mathit{L}}}^{\prime}}/{{\mathit{d}}}\end{equation*}\end{document}e−dt−te+\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{\overline{{\mathit{s}}}_{{\mathit{L}}}^{\prime}}/{{\mathit{d}}}\end{equation*}\end{document}, where \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L′=\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}{ \left \left(\overline{{\mathit{s}}}_{{\mathit{L}}}^{\prime}\right) \right }/{{\mathit{U}} \left \left(0\right) \right }\end{equation*}\end{document}. In this equation, fL(te) represents the fraction of labeled DNA at the time, te, that D-glucose infusion ends. While the proliferation rate does not appear in the equations for fL(t), it can be estimated using the steady state condition p = d − s/T or in the case of DNA, p = d − (sU+ sL)/U(0); thus, p>d−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}U. Because we expect \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L<\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L′, p<d−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}U+\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}L′, these two estimates of p turn out to be close to each other and in Table I we report their mean. The initial slope of the labeling curve is d−\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}\overline{{\mathit{s}}}\end{equation*}\end{document}U, which to a good approximation is p. When D-glucose is administered for a second or third time to the same patient, the expressions given above for fL(t) are modified to account for any existing labeled DNA at the start of the infusion. Also, when the measurements of total CD4+ and CD8+ T cells indicate a significant change in the population, we relax the assumption of steady state. In this case, we used the solution of equation 1 to determine the total amount of DNA at time t to be used in the calculation of the fraction of labeled DNA. Finally, because most T cells are in tissues, we assumed that after labeling there would be a delay τ before labeled DNA first appeared in blood. Further, when D-glucose administration ended at time te, we also assumed labeled DNA would continue to accumulate in the blood until time te + τ. Thus, on the right hand side of the equations given above for fL(t), t should be replaced by t − τ, and for 0< t < τ, fL(t) = 0. To model monocyte kinetics, we assume no proliferation occurs in the periphery, i.e., p = 0 in equations 1–3, and d is interpreted as a rate of monocyte export out of blood.

Bottom Line: In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls.Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy.Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

View Article: PubMed Central - PubMed

Affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA.

ABSTRACT
The mechanism of CD4(+) T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1-infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8(+) T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4(+) and CD8(+) cell populations were substantially reduced by 5-11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

Show MeSH
Related in: MedlinePlus