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Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy.

Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, He Y, Jin X, Tuttleton S, Vesanen M, Spiegel H, Kost R, van Lunzen J, Stellbrink HJ, Wolinsky S, Borkowsky W, Palumbo P, Kostrikis LG, Ho DD - J. Exp. Med. (1999)

Bottom Line: By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter.Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers.In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment.

View Article: PubMed Central - PubMed

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

ABSTRACT
The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.

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Related in: MedlinePlus

(A) Changes in α1 circle numbers in 74 individuals treated with combination antiretroviral therapy. Both acutely and chronically infected individuals were stratified into two different categories according to their pretreatment α1 circle values: ≤2,200 (•) or >2,200 (○) per 106 PBMCs. (B) HAART-associated changes in mean CD4+ (▪), CD8+ (•), CD4+CD45RA+CD62L+ (▴), and CD8+CD45RA+CD62L+ (♦) T cell counts as well as changes in the mean α1 circle numbers (○).
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Figure 4: (A) Changes in α1 circle numbers in 74 individuals treated with combination antiretroviral therapy. Both acutely and chronically infected individuals were stratified into two different categories according to their pretreatment α1 circle values: ≤2,200 (•) or >2,200 (○) per 106 PBMCs. (B) HAART-associated changes in mean CD4+ (▪), CD8+ (•), CD4+CD45RA+CD62L+ (▴), and CD8+CD45RA+CD62L+ (♦) T cell counts as well as changes in the mean α1 circle numbers (○).

Mentions: We studied the impact of HAART on the number of α1 circles in PBMCs of 74 previously drug-naive individuals (mean age, 36; ages ranged from 24 to 59). 27 patients began treatment within the first 90 d of their HIV-1 infection, whereas 47 were chronically infected for varying lengths of time. DNA extracted from sequential PBMC samples (generally ≥5) from each case were assayed for α1 circles. Variable patterns of response to HAART were observed, in contrast to the nearly complete response rate previously reported 18. As displayed in Fig. 4 A, those individuals with baseline values of >2,200 α1 circles/106 PBMCs (the median value for age-matched normal controls) in general did not have a rise in α1 circle numbers while receiving HAART. In contrast, individuals with baseline values ≤2,200 typically showed increases during treatment. These differences were quantified by calculating the slope of the regression line for all α1 circle data points from each individual. For example, in the cohort of chronically infected individuals, the mean slope of the change in α1 circles during HAART was +1.13/yr for those with a low baseline value and −0.51/year for those with a normal baseline value (Fig. 4 A). That the overall slope difference between individuals with low baselines and those with normal values was statistically significant (P < 0.05, t test) suggests that an increase in the number of RTEs during HAART is seen primarily in individuals with an existing impairment.


Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy.

Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, He Y, Jin X, Tuttleton S, Vesanen M, Spiegel H, Kost R, van Lunzen J, Stellbrink HJ, Wolinsky S, Borkowsky W, Palumbo P, Kostrikis LG, Ho DD - J. Exp. Med. (1999)

(A) Changes in α1 circle numbers in 74 individuals treated with combination antiretroviral therapy. Both acutely and chronically infected individuals were stratified into two different categories according to their pretreatment α1 circle values: ≤2,200 (•) or >2,200 (○) per 106 PBMCs. (B) HAART-associated changes in mean CD4+ (▪), CD8+ (•), CD4+CD45RA+CD62L+ (▴), and CD8+CD45RA+CD62L+ (♦) T cell counts as well as changes in the mean α1 circle numbers (○).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195623&req=5

Figure 4: (A) Changes in α1 circle numbers in 74 individuals treated with combination antiretroviral therapy. Both acutely and chronically infected individuals were stratified into two different categories according to their pretreatment α1 circle values: ≤2,200 (•) or >2,200 (○) per 106 PBMCs. (B) HAART-associated changes in mean CD4+ (▪), CD8+ (•), CD4+CD45RA+CD62L+ (▴), and CD8+CD45RA+CD62L+ (♦) T cell counts as well as changes in the mean α1 circle numbers (○).
Mentions: We studied the impact of HAART on the number of α1 circles in PBMCs of 74 previously drug-naive individuals (mean age, 36; ages ranged from 24 to 59). 27 patients began treatment within the first 90 d of their HIV-1 infection, whereas 47 were chronically infected for varying lengths of time. DNA extracted from sequential PBMC samples (generally ≥5) from each case were assayed for α1 circles. Variable patterns of response to HAART were observed, in contrast to the nearly complete response rate previously reported 18. As displayed in Fig. 4 A, those individuals with baseline values of >2,200 α1 circles/106 PBMCs (the median value for age-matched normal controls) in general did not have a rise in α1 circle numbers while receiving HAART. In contrast, individuals with baseline values ≤2,200 typically showed increases during treatment. These differences were quantified by calculating the slope of the regression line for all α1 circle data points from each individual. For example, in the cohort of chronically infected individuals, the mean slope of the change in α1 circles during HAART was +1.13/yr for those with a low baseline value and −0.51/year for those with a normal baseline value (Fig. 4 A). That the overall slope difference between individuals with low baselines and those with normal values was statistically significant (P < 0.05, t test) suggests that an increase in the number of RTEs during HAART is seen primarily in individuals with an existing impairment.

Bottom Line: By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter.Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers.In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment.

View Article: PubMed Central - PubMed

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

ABSTRACT
The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.

Show MeSH
Related in: MedlinePlus