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Abstract
ANALYSIS OF T-LYMPHOCYTE TURNOVER RATES USING NOVEL MODELS FOR THE STUDY OF DEUTERATED GLUCOSE
RIBEIRO R, MOHRI H, HO D, PERELSON A
Background: The elucidation of T-cell turnover dynamics is crucial for an understanding of HIV pathogenesis. New methods to measure that turnover have been developed, including the use of deuterated glucose. However a proper interpretation of the experimental results requires the development of mathematical models, which provide a quantitative description of the system. Methods: We have formulated a new mathematical model specific for the interpretation of deuterated glucose experiments. This model differs from previous models in that it explicitly accounts for the labeling of DNA instead of cells. We have also extended this model to address the issue of different states of T-cell activation. Results: Model fitting shows that the rate of production is significantly elevated in HIV-infected patients versus controls, both in CD4+ and CD8+ T-cells (0.025 vs. 0.004, p<0.02 for CD4+, and 0.023 vs. 0.003, p<0.01 for CD8+). In HIV infected patients, the death rate of CD4+ T-cells is also significantly increased (0.13 vs. 0.044, p<0.04), but that of CD8+ T-cells is not (0.050 vs. 0.043, p>0.5). The rate of activation of CD4+ T-cells is also higher in HIV infected patients than in healthy individuals (0.0056 vs. 0.0026, p<0.004). And, indeed, the estimated fraction of activated cells correlates significantly with measurements of Ki67+ stained cells (r=0.79, p<0.0005). This state of higher fractional turnover of both lymphocyte compartments is slowly resolved during therapy, and after one year of HAART the production, death and activation rates are only slightly elevated in relation to controls. Conclusions: HIV infection leads to an increased state of immune activation, with higher average turnovers. The death rate of CD4+ T-cells is elevated in HIV-infected individuals in relation to controls, whereas in CD8+ T-cells that is not the case, suggesting an enhanced destruction of CD4+ by virus infection. Treatment lowers all correlates of activation to nearly normal levels.
The 1st. IAS Conference on HIV Pathogenesis and Treatment
Abstract no.
81
Suggested Citation
"RIBEIROR, et al.
ANALYSIS OF T-LYMPHOCYTE TURNOVER RATES USING NOVEL MODELS FOR THE STUDY OF DEUTERATED GLUCOSE.
Oral Presentation:
The 1st. IAS Conference on HIV Pathogenesis and Treatment
:
Abstract no.
81"
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