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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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Correlation among parameters. (A) Correlation of the fraction of CD4+ and CD8+ lymphocytes expressing Ki67 antigen or TUNEL with p, the lymphocyte proliferation rate. Significant correlations were observed between values of p and fractions of Ki67+ CD4+ T cells (r = 0.91, P value <0.00001) or CD8+ T cells (r = 0.90, P value <0.00001), as well as between values of p and fractions of TUNEL+ CD4+ T cells (r = 0.79, P value = 0.00006) or CD8+ T cells (r = 0.87, P value <0.00001). Note that these regression lines are parallel in CD8+ lymphocytes (P value = 0.86), but not in CD4+ lymphocytes (P value = 0.0017). (B) Significant correlation between baseline CD4+ T cell count or plasma viral load and values of p, fraction of Ki67+ cells, or fraction of TUNEL+ cells in both CD4+ and CD8+ cell populations (P values <0.05). Results of patients with undetectable plasma viral load are plotted as of 50 copies/ml (detection limit).
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fig5: Correlation among parameters. (A) Correlation of the fraction of CD4+ and CD8+ lymphocytes expressing Ki67 antigen or TUNEL with p, the lymphocyte proliferation rate. Significant correlations were observed between values of p and fractions of Ki67+ CD4+ T cells (r = 0.91, P value <0.00001) or CD8+ T cells (r = 0.90, P value <0.00001), as well as between values of p and fractions of TUNEL+ CD4+ T cells (r = 0.79, P value = 0.00006) or CD8+ T cells (r = 0.87, P value <0.00001). Note that these regression lines are parallel in CD8+ lymphocytes (P value = 0.86), but not in CD4+ lymphocytes (P value = 0.0017). (B) Significant correlation between baseline CD4+ T cell count or plasma viral load and values of p, fraction of Ki67+ cells, or fraction of TUNEL+ cells in both CD4+ and CD8+ cell populations (P values <0.05). Results of patients with undetectable plasma viral load are plotted as of 50 copies/ml (detection limit).

Mentions: We next compared the values of p and d derived for all subjects from the three labeling studies to the expression of two lymphocyte markers: Ki67, a nuclear antigen expressed exclusively in cells in late G1, S, G2, and M phases of the cell cycle (20), and TUNEL, an indicator of apoptosis (21). As shown in Fig. 5 A, there was a direct correlation between the value of p and the fraction of cells positive for Ki67 or TUNEL. These correlations, seen in both CD4+ and CD8+ lymphocytes, were strong (correlation coefficients between 0.79 and 0.91) and statistically significant (P values <0.002). The value of d, however, was only weakly correlated with these markers (P value <0.05), and in CD8+ T cells the correlation between d and TUNEL was not significant (data not shown). Nevertheless, these results suggest that Ki67 and TUNEL expression in blood cells could serve as simple and reasonably reliable surrogate markers for lymphocyte proliferation in vivo.


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)

Correlation among parameters. (A) Correlation of the fraction of CD4+ and CD8+ lymphocytes expressing Ki67 antigen or TUNEL with p, the lymphocyte proliferation rate. Significant correlations were observed between values of p and fractions of Ki67+ CD4+ T cells (r = 0.91, P value <0.00001) or CD8+ T cells (r = 0.90, P value <0.00001), as well as between values of p and fractions of TUNEL+ CD4+ T cells (r = 0.79, P value = 0.00006) or CD8+ T cells (r = 0.87, P value <0.00001). Note that these regression lines are parallel in CD8+ lymphocytes (P value = 0.86), but not in CD4+ lymphocytes (P value = 0.0017). (B) Significant correlation between baseline CD4+ T cell count or plasma viral load and values of p, fraction of Ki67+ cells, or fraction of TUNEL+ cells in both CD4+ and CD8+ cell populations (P values <0.05). Results of patients with undetectable plasma viral load are plotted as of 50 copies/ml (detection limit).
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Correlation among parameters. (A) Correlation of the fraction of CD4+ and CD8+ lymphocytes expressing Ki67 antigen or TUNEL with p, the lymphocyte proliferation rate. Significant correlations were observed between values of p and fractions of Ki67+ CD4+ T cells (r = 0.91, P value <0.00001) or CD8+ T cells (r = 0.90, P value <0.00001), as well as between values of p and fractions of TUNEL+ CD4+ T cells (r = 0.79, P value = 0.00006) or CD8+ T cells (r = 0.87, P value <0.00001). Note that these regression lines are parallel in CD8+ lymphocytes (P value = 0.86), but not in CD4+ lymphocytes (P value = 0.0017). (B) Significant correlation between baseline CD4+ T cell count or plasma viral load and values of p, fraction of Ki67+ cells, or fraction of TUNEL+ cells in both CD4+ and CD8+ cell populations (P values <0.05). Results of patients with undetectable plasma viral load are plotted as of 50 copies/ml (detection limit).
Mentions: We next compared the values of p and d derived for all subjects from the three labeling studies to the expression of two lymphocyte markers: Ki67, a nuclear antigen expressed exclusively in cells in late G1, S, G2, and M phases of the cell cycle (20), and TUNEL, an indicator of apoptosis (21). As shown in Fig. 5 A, there was a direct correlation between the value of p and the fraction of cells positive for Ki67 or TUNEL. These correlations, seen in both CD4+ and CD8+ lymphocytes, were strong (correlation coefficients between 0.79 and 0.91) and statistically significant (P values <0.002). The value of d, however, was only weakly correlated with these markers (P value <0.05), and in CD8+ T cells the correlation between d and TUNEL was not significant (data not shown). Nevertheless, these results suggest that Ki67 and TUNEL expression in blood cells could serve as simple and reasonably reliable surrogate markers for lymphocyte proliferation in vivo.

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