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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 T lymphocytes. The data of healthy controls (C1–C4) versus HIV-1–infected patients (P1–P7) are shown in each graph. The period of D-glucose administration is indicated by a box (top left corner). The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model.
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fig3: Sequential changes in the fraction of labeled DNA in blood T lymphocytes. The data of healthy controls (C1–C4) versus HIV-1–infected patients (P1–P7) are shown in each graph. The period of D-glucose administration is indicated by a box (top left corner). The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model.

Mentions: We then turned our attention to CD3+CD4+ and CD3+CD8+ lymphocytes that have been purified to >98% homogeneity by a cell sorter from each blood specimen. Again, every cellular DNA sample was examined for deuterium incorporation into the dA fraction (9, 10). From the results summarized in Fig. 3 , it is readily apparent that the labeling and delabeling profiles in the four normal subjects were rather uniform, with CD4+ T cells showing slightly higher levels of deuterium incorporation than CD8+ T cells. Labeled DNA became detectable with a mean time lag of 0.5 d, and its level increased slowly during D-glucose administration followed by a gradual decrease thereafter. The peak fraction of labeled DNA did not exceed 0.04 in either cell population. In contrast, the results are substantially different in seven HIV-1–infected patients who were not on antiretroviral therapy. Their rates of rise and fall of labeled DNA were obviously greater than those observed in normal controls, even in P5 who was given D-glucose for 4.3 d. Likewise, the peak labeling was consistently higher in infected individuals, with some reaching a labeled fraction of ∼0.20. Interestingly, the lowest deuterium incorporation in infected subjects was seen in P3, the one with the lowest viral load (Table I). There was no consistent relationship noted when comparing labeling profiles in CD4+ versus CD8+ lymphocytes. Overall, the findings in Fig. 3 provide a qualitative impression that lymphocyte turnover is substantially more rapid in infected patients than in normal persons.


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 T lymphocytes. The data of healthy controls (C1–C4) versus HIV-1–infected patients (P1–P7) are shown in each graph. The period of D-glucose administration is indicated by a box (top left corner). The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Sequential changes in the fraction of labeled DNA in blood T lymphocytes. The data of healthy controls (C1–C4) versus HIV-1–infected patients (P1–P7) are shown in each graph. The period of D-glucose administration is indicated by a box (top left corner). The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model.
Mentions: We then turned our attention to CD3+CD4+ and CD3+CD8+ lymphocytes that have been purified to >98% homogeneity by a cell sorter from each blood specimen. Again, every cellular DNA sample was examined for deuterium incorporation into the dA fraction (9, 10). From the results summarized in Fig. 3 , it is readily apparent that the labeling and delabeling profiles in the four normal subjects were rather uniform, with CD4+ T cells showing slightly higher levels of deuterium incorporation than CD8+ T cells. Labeled DNA became detectable with a mean time lag of 0.5 d, and its level increased slowly during D-glucose administration followed by a gradual decrease thereafter. The peak fraction of labeled DNA did not exceed 0.04 in either cell population. In contrast, the results are substantially different in seven HIV-1–infected patients who were not on antiretroviral therapy. Their rates of rise and fall of labeled DNA were obviously greater than those observed in normal controls, even in P5 who was given D-glucose for 4.3 d. Likewise, the peak labeling was consistently higher in infected individuals, with some reaching a labeled fraction of ∼0.20. Interestingly, the lowest deuterium incorporation in infected subjects was seen in P3, the one with the lowest viral load (Table I). There was no consistent relationship noted when comparing labeling profiles in CD4+ versus CD8+ lymphocytes. Overall, the findings in Fig. 3 provide a qualitative impression that lymphocyte turnover is substantially more rapid in infected patients than in normal persons.

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