Session 44Poster Presentations Lymphocyte Dynamics Session Day and Time: Wednesday 1:30 - 3:30 pm Room: Hall D
331 Modeling the Dynamics of T-cells and TREC After Early and Late Treatment of HIV-1 Infection R. M. Ribeiro*1, S. Lewin2, A. S. Perelson1 1Los Alamos Natl Lab, NM and 2Univ of Melbourne, Australia
Background: The immune processes involved in lymphocyte changes observed under HIV therapy are still controversial. In particular, the relative contributions of decreases in activation (as measured by death and proliferation rates), lymphocyte redistribution, and thymic output are not well understood.
Methods: To quantify these factors, we developed a mathematical model of the dynamics of cells containing T-cell receptor excision circles (TREC) and cells that do not contain TREC. We consider changes in thymic output, cell proliferation, cell death, activation, and the dynamics of redistribution between periphery and tissue. We analyzed the model analytically and using numerical simulations, and determined the changes in lymphocyte counts, TREC/ml and TREC/million cells with therapy. We compared the results of the model with treatment data of primary (PHI) and chronic (CHI) HIV-1 infection.
Results: To validate the model, we showed it could reproduce the expected changes in TREC and total lymphocytes during aging of healthy individuals. We then analyzed the changes in TREC with therapy. After therapy of PHI there is no significant changes in TREC/million cells and only a transient increase in TREC/ml. However, in CHI, there is an increase in both TREC/million cells and TREC/ml. The model is able to reproduce these results, and it indicates that redistribution of cells from tissue to peripheral blood is enough to explain the observed changes in TREC and lymphocytes following therapy of PHI: A therapy driven 25% change in the recirculation parameters explains the increase in T-cell numbers, in the absence of changes in TREC content. By contrast, after therapy of CHI, when CD4+ counts are low, changes in recirculation parameters are not enough to explain the increase of TREC in the periphery. In CHI, the model shows that increases in CD4+ T-cells are a consequence of the reduction in the death rate of lymphocytes, and perhaps increases in thymic output (by about 50%). The patterns of change in TREC/ml and TREC/million cells give independent information about T-cell dynamics following effective antiviral therapy.
Conclusions: This model is a new framework to study the effects of antiviral therapy on lymphocytes and gives insight into the different mechanisms operating early and late in HIV-1 infection. The model identifies new ways to assess early impact of therapy on lymphocyte redistribution by comparing changes in both TREC/ml and TREC/million cells.
