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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

Sequential changes in the fraction of labeled DNA in blood monocytes. The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model. The calculated half-lives (t1/2) for monocytes in blood are indicated.
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fig2: Sequential changes in the fraction of labeled DNA in blood monocytes. The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model. The calculated half-lives (t1/2) for monocytes in blood are indicated.

Mentions: To ensure that the new labeling technique would yield reliable results, we first examined the incorporation of deuterium into the DNA of monocytes since their half-life (t1/2) or transit time in blood had been defined (16). Monocytes were purified from three normal subjects and two patients using an anti-CD14 mAb coupled to Dynabeads. DNA was then extracted from each cell preparation, processed, and tested for the degree of deuterium incorporation into the dA fraction using gas chromatography and mass spectroscopy. As shown in Fig. 2 , labeled DNA became detectable in blood after a delay of ∼2 d. Thereafter, the fraction of labeled DNA rose rapidly, reaching a peak of 0.60–0.85 before falling promptly upon the cessation of D-glucose infusion. These results were then analyzed using a simple mathematical model that assumes monocytes label in the bone marrow and then appear in blood with some time delay before moving into tissues as macrophages. Fitting the data to the model (Fig. 2) yielded a t1/2 of monocytes in blood of ∼2 d, regardless of HIV-1 infection status, in close agreement with published results (16) and thereby validating the D-glucose labeling method (9, 10, 17).


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)

Sequential changes in the fraction of labeled DNA in blood monocytes. The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model. The calculated half-lives (t1/2) for monocytes in blood are indicated.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Sequential changes in the fraction of labeled DNA in blood monocytes. The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model. The calculated half-lives (t1/2) for monocytes in blood are indicated.
Mentions: To ensure that the new labeling technique would yield reliable results, we first examined the incorporation of deuterium into the DNA of monocytes since their half-life (t1/2) or transit time in blood had been defined (16). Monocytes were purified from three normal subjects and two patients using an anti-CD14 mAb coupled to Dynabeads. DNA was then extracted from each cell preparation, processed, and tested for the degree of deuterium incorporation into the dA fraction using gas chromatography and mass spectroscopy. As shown in Fig. 2 , labeled DNA became detectable in blood after a delay of ∼2 d. Thereafter, the fraction of labeled DNA rose rapidly, reaching a peak of 0.60–0.85 before falling promptly upon the cessation of D-glucose infusion. These results were then analyzed using a simple mathematical model that assumes monocytes label in the bone marrow and then appear in blood with some time delay before moving into tissues as macrophages. Fitting the data to the model (Fig. 2) yielded a t1/2 of monocytes in blood of ∼2 d, regardless of HIV-1 infection status, in close agreement with published results (16) and thereby validating the D-glucose labeling method (9, 10, 17).

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