We hypothesized that HIV-1-mediated T-cell loss might induce the production of factors that are capable of stimulating lymphocyte development and expansion. Here we perform cross-sectional (n = 168) and longitudinal (n = 11) analyses showing that increased circulating levels of interleukin (IL)-7 are strongly associated with CD4+ T lymphopenia in HIV-1 disease. Using immunohistochemistry with quantitative image analysis, we demonstrate that IL-7 is produced by dendritic-like cells within peripheral lymphoid tissues and that IL-7 production by these cells is greatly increased in lymphocyte-depleted tissues. We propose that IL-7 production increases as part of a homeostatic response to T-cell depletion.

Poor CD4 T cell increases observed in some patients with good virologic response to HAART may be caused by failure of thymic T cell production.

Growth hormone (GH) is an underappreciated but important regulator of T cell development that can reverse age-related declines in thymopoiesis in rodents. Here, we report findings of a prospective randomized study examining the effects of GH on the immune system of HIV-1-infected adults. GH treatment was associated with increased thymic mass. In addition, GH treatment enhanced thymic output, as measured by both the frequency of T cell receptor rearrangement excision circles in circulating T cells and the numbers of circulating naive and total CD4 + T cells. These findings provide compelling evidence that GH induces de novo T cell production and may, accordingly, facilitate CD4 + T cell recovery in HIV-1-infected adults. Further, these randomized, prospective data have shown that thymic involution can be pharmacologically reversed in humans, suggesting that immune-based therapies could be used to enhance thymopoiesis in immunodeficient individuals.

In the early phase of HIV-1 infection, there was a migration of DC to LT comparable to that found in acute EBV infection. The infiltration of DC in LT in acute EBV infection was accompanied by upregulation of CD80 and CD86 expression, which did not occur in aHI. This co-stimulatory defect in aHI may have an impact on the development of HIV-1-specific T cell immunity.

GH has significant effects on the human immune system, including the reversal of thymic atrophy in HIV-1-infected adults. De-novo T cell production may thus be inducible in immunodeficient adults.

Although the literature contains many studies on the function of UCP3, its role is still being debated. It has been hypothesized that UCP3 may mediate lipid hydroperoxide (LOOH) translocation across the mitochondrial inner membrane (MIM), thus protecting the mitochondrial matrix from this very aggressive molecule. However, no experiments on mitochondria have provided evidence in support of this hypothesis. Here, using mitochondria isolated from UCP3-null mice and their wild-type littermates, we demonstrate the following. (i) In the absence of free fatty acids, proton conductance did not differ between wild-type and UCP3-null mitochondria. Addition of arachidonic acid (AA) to such mitochondria induced an increase in proton conductance, with wild-type mitochondria showing greater enhancement. In wild-type mitochondria, the uncoupling effect of AA was significantly reduced both when the release of O 2 . in the matrix was inhibited and when the formation of LOOH was inhibited. In UCP3-null mitochondria, however, the uncoupling effect of AA was independent of the above mechanisms. (ii) In the presence of AA, wild-type mitochondria released significantly more LOOH compared with UCP3-null mitochondria. This difference was abolished both when UCP3 was inhibited by GDP and under a condition in which there was reduced LOOH formation on the matrix side of the MIM. These data demonstrate that UCP3 is involved both in mediating the translocation of LOOH across the MIM and in LOOH-dependent mitochondrial uncoupling.Uncoupling proteins (UCPs) 3 are homologous proteins belonging to a subfamily of mitochondrial anion carriers. Although both the function and mechanism of action of the first cloned UCP (UCP1) are quite well established, those of the UCP1 homologs are still far from clear. Because of its homology to UCP1 and its prevalent skeletal muscle expression, UCP3 has been hypothesized to be a thermogenic protein. However, the literature contains conflicting results, and an increased expression of UCP3 has not always been associated with mitochondrial uncoupling. This may suggest that uncoupling is not its primary function but rather a consequence of its real function (for reviews, see Refs.

NCT01400412.

Growth hormone (GH) has been shown to have significant positive effects on hemato-lymphopoiesis in rodent models and, more recently, to increase thymic mass and circulating naïve CD4 + T cells in humans infected with the human immunodeficiency virus, type 1. To determine whether the latter effects on human T lymphopoiesis might be due, at least in part, to effects on the bone marrow (BM), we examined the specific effects of GH and its proximal mediator, insulin-like growth factor I (IGF-I), on human multilineage hematopoiesis in fetal BM (FBM). Using in vitro analysis, we found that GH and IGF-I each stimulated the expansion of primitive multilineage CD34 + CD38 − hematopoietic progenitor cells and increased yields of several hematopoietic subpopulations, including CD34 + CD38 + CD10 + lymphoid progenitor cells. Additionally, GH and IGF-I had direct effects on FBM stromal elements,inducing the expansion of myeloid-like CD45