We show a representative example of an uninfected monkey (U1458), of a SIV-infected monkey with a low viral load (L1394), and an infected monkey with a high SIV load (H1284). The MBC of this kinetically heterogeneous cell population model can be defined Tg very similarly to above. death (i.e. kinetic heterogeneity). We fit the extended model to previously published BrdU data from memory T lymphocytes in simian immunodeficiency virus-infected and uninfected macaques, and find that the model describes the data with at least the same quality as previous models. Because the same model predicts a modest decline in the MBC of BrdU+ cells, which is consistent with experimental observations, BrdU dilution seems a natural explanation for the observed down-slopes in self-renewing populations. experiments this has mostly been replaced by BrdU and deuterium. Another important labelling technique used for tracking the division history of lymphocytes is carboxyfluorescein succinimidyl ester (CFSE). CFSE is a fluorescent dye which does not label DNA, but binds cytoplasmic proteins and equally dilutes upon cell division. Most experiments with CFSE rely on the adoptive transfer of CFSE-labelled lymphocytes [1,2]. The interpretation on CFSE data is complicated, and several dedicated mathematical models have been developed to quantify lymphocyte Cediranib maleate turnover using CFSE data [3C10]. BrdU has been used for decades in mice [11,12], and more recently in monkeys [13C15]. Because of potential problems with toxicity, it has been used infrequently in humans [16C20], and only over Cediranib maleate short-term periods. Indeed, it has been reported that BrdU is toxic for various cell types, and may trigger an injury response leading to activation and division [21,22], which would perturb the normal population dynamics. Other laboratories found little toxicity of BrdU [23,24], and BrdU data have hitherto been interpreted under the assumption that BrdU does not influence the rates of cell proliferation or death. In the presence of BrdU, Cediranib maleate an unlabelled cell (= (: and 1.1 where and are (daily) division and death rates, and and are the numbers of unlabelled and labelled cells, and . To fit this model to BrdU data, one has to define the fraction of labelled cells, i.e. , and derive the differential equation for the fraction of labelled cells from equation?(1.1). Straightforward calculus reveals that d= (d? (and dfrom equation?(1.1) finds that d= 2= 0 during the de-labelling phase. Thus, the death rate cancels and the fraction of labelled cells is expected to increase with an initial up-slope of 2during the labelling phase. From the d= 0 result, one expects that the down-slope isat least initiallyflat during the de-labelling phase. For most cell types, the fraction of BrdU+ cells indeed increases during the labelling phase, but tends to decrease during the de-labelling phase, which is at conflict with the d= 0 result. To solve this problem, different authors have proposed different solutions. Several authors [13,25C27] allowed for an external source of cells, for example coming from the thymus or from a compartment of quiescent cells, and by allowing the generation of unlabelled cells during the de-labelling phase they were able to explain the observed down-slopes. Others [28C30] argued that labelled cells have recently divided, and that recently divided cells should have a faster death rate than non-divided unlabelled cells, which also allows for a decline of the fraction of BrdU+ cells. Several authors in the field of immunology [23,28,31] and in the field of haematopoietic stem cells [21,24,32] have argued that the loss of BrdU+ cells can be explained by BrdU dilution during the de-labelling.