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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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Comparison of T cell kinetics before and during antiretroviral therapy. (A) Changes in viral load as well as CD4+ and CD8+ lymphocyte counts during treatment. The data from each patient are represented by a unique symbol. The periods of repeat D-glucose labeling studies are indicated by rectangular boxes marked by each patient's identification number followed by the episode of labeling. (B) Fraction of labeled DNA in CD4+ and CD8+ lymphocytes from P1–P5 during the first (pretreatment) (○), second (gray square), and third (▴) episodes of labeling. The duration of D-glucose administration is indicated by a box in each graph. Again, the data points are represented by symbols, and the lines show the best fit of the data to the mathematical model. Note that the fraction of labeled DNA on day 0 in the second or third episode is not zero because of residual label from the previous labeling episode. (C) Changes in the estimated values of p (proliferation rate) and d (death rate) with antiretroviral therapy.
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fig4: Comparison of T cell kinetics before and during antiretroviral therapy. (A) Changes in viral load as well as CD4+ and CD8+ lymphocyte counts during treatment. The data from each patient are represented by a unique symbol. The periods of repeat D-glucose labeling studies are indicated by rectangular boxes marked by each patient's identification number followed by the episode of labeling. (B) Fraction of labeled DNA in CD4+ and CD8+ lymphocytes from P1–P5 during the first (pretreatment) (○), second (gray square), and third (▴) episodes of labeling. The duration of D-glucose administration is indicated by a box in each graph. Again, the data points are represented by symbols, and the lines show the best fit of the data to the mathematical model. Note that the fraction of labeled DNA on day 0 in the second or third episode is not zero because of residual label from the previous labeling episode. (C) Changes in the estimated values of p (proliferation rate) and d (death rate) with antiretroviral therapy.

Mentions: Five of the infected patients were reevaluated to assess the impact of successful antiretroviral therapy on lymphocyte dynamics. A potent four-drug regimen was initiated in P1 through P5 several weeks after the completion of their first labeling study. As shown in Fig. 4 A, plasma viremia dropped precipitously in each case, eventually reaching undetectable levels in those patients treated beyond 150 d. At the same time, the CD4+ T cell numbers of these patients showed an increasing trend (Fig. 4 A). The second episode of D-glucose labeling was carried out in these five patients beginning on days 35–77 of treatment. P4 and P5 left the study after finishing the second study, whereas P1, P2, and P3 went on to have the third episode of D-glucose labeling starting on days 245–375 of treatment when plasma viral load was persistently undetectable save for one transient “blip” in P2.


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)

Comparison of T cell kinetics before and during antiretroviral therapy. (A) Changes in viral load as well as CD4+ and CD8+ lymphocyte counts during treatment. The data from each patient are represented by a unique symbol. The periods of repeat D-glucose labeling studies are indicated by rectangular boxes marked by each patient's identification number followed by the episode of labeling. (B) Fraction of labeled DNA in CD4+ and CD8+ lymphocytes from P1–P5 during the first (pretreatment) (○), second (gray square), and third (▴) episodes of labeling. The duration of D-glucose administration is indicated by a box in each graph. Again, the data points are represented by symbols, and the lines show the best fit of the data to the mathematical model. Note that the fraction of labeled DNA on day 0 in the second or third episode is not zero because of residual label from the previous labeling episode. (C) Changes in the estimated values of p (proliferation rate) and d (death rate) with antiretroviral therapy.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Comparison of T cell kinetics before and during antiretroviral therapy. (A) Changes in viral load as well as CD4+ and CD8+ lymphocyte counts during treatment. The data from each patient are represented by a unique symbol. The periods of repeat D-glucose labeling studies are indicated by rectangular boxes marked by each patient's identification number followed by the episode of labeling. (B) Fraction of labeled DNA in CD4+ and CD8+ lymphocytes from P1–P5 during the first (pretreatment) (○), second (gray square), and third (▴) episodes of labeling. The duration of D-glucose administration is indicated by a box in each graph. Again, the data points are represented by symbols, and the lines show the best fit of the data to the mathematical model. Note that the fraction of labeled DNA on day 0 in the second or third episode is not zero because of residual label from the previous labeling episode. (C) Changes in the estimated values of p (proliferation rate) and d (death rate) with antiretroviral therapy.
Mentions: Five of the infected patients were reevaluated to assess the impact of successful antiretroviral therapy on lymphocyte dynamics. A potent four-drug regimen was initiated in P1 through P5 several weeks after the completion of their first labeling study. As shown in Fig. 4 A, plasma viremia dropped precipitously in each case, eventually reaching undetectable levels in those patients treated beyond 150 d. At the same time, the CD4+ T cell numbers of these patients showed an increasing trend (Fig. 4 A). The second episode of D-glucose labeling was carried out in these five patients beginning on days 35–77 of treatment. P4 and P5 left the study after finishing the second study, whereas P1, P2, and P3 went on to have the third episode of D-glucose labeling starting on days 245–375 of treatment when plasma viral load was persistently undetectable save for one transient “blip” in P2.

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