HIV infection is characterized by a brisk immune activation that plays an important role in the CD4 depletion and immune dysfunction of patients with AIDS. The mechanism underlying this activation is poorly understood. In the current study, we tested the hypothesis that this activation is the net product of two distinct pathways: the inflammatory response to HIV infection and the homeostatic response to CD4 T cell depletion. Using ex vivo BrdU incorporation of PBMCs from 284 patients with different stages of HIV infection, we found that CD4 proliferation was better predicted by the combination of CD4 depletion and HIV viral load (R 2 ‫؍‬ 0.375, P < 0.001) than by either parameter alone (CD4 T cell counts, R 2 ‫؍‬ 0.202, P < 0.001; HIV viremia, R 2 ‫؍‬ 0.302, P < 0.001). Interestingly, CD8 T cell proliferation could be predicted by HIV RNA levels alone (R 2 ‫؍‬ 0.334, P < 0.001) and this predictive value increased only slightly (R 2 ‫؍‬ 0.346, P < 0.001) when CD4 T cell depletion was taken into account. Consistent with the hypothesis that CD4 T cell proliferation is driven by IL-7 as a homeostatic response to CD4 T cell depletion, levels of phosphorylated STAT-5 were found to be elevated in naive subsets of CD4 and CD8 T cells from patients with HIV infection and in the central memory subset of CD4 T cells. Taken together these data demonstrate that at least two different pathways lead to immune activation of T cells in patients with HIV infection and these pathways differentially influence CD4 and CD8 T cell subsets.CD4 T cell homeostasis ͉ IL-7 ͉ STAT-5

Since the earliest days of the HIV epidemic, the number of CD4 ؉ T cells per unit volume of blood has been recognized as a major prognostic factor for the development of AIDS in persons with HIV infection. It has also been generally accepted that approximately 2% of total body lymphocytes circulate in the blood. In the present study, we have used a nondepleting humanized anti-CD4 monoclonal antibody labeled with the gamma emitter indium-111 to visualize the CD4 ؉ T-cell pool in vivo in nonhuman primates with simian HIV infection. A strong correlation was noted between radiotracer uptake in spleen, tonsil, axillary lymph nodes, and peripheral blood CD4 T-cell counts ( ‫؍‬ 0.75, 0.93, and 0.85, respectively, P < .005). The relationship between radiotracer retention in lymphoid tissues and CD4 ؉ T-cell counts in the circulation was governed by an exponential law. These data provide an estimate for the total number of lymphocytes in the body as being between 1.9 and 2.9 ؋ 10 12 and suggest that the partition between peripheral blood and lymphoid tissue is between 0.3% and 0.5%. (Blood. 2009; 114:328-337)

Our current knowledge on the antiviral efficacy, dosing, and toxicity of available highly active antiretroviral therapy regimens is mostly derived from plasma or blood kinetics of anti-human immunodeficiency virus (anti-HIV) drugs. However, the blood comprises only 2% of the total target cells in the body. Tissue drug levels may differ substantially from corresponding plasma levels, and drug distribution processes may be characterized by high intertissue variability, leading to suboptimal target site concentrations and the potential risk for therapeutic failures. Positron emission tomography has greatly expanded the scope of the pharmacokinetic measurements that can be performed noninvasively in animal models or humans. We have prepared [

IL-7 is essential for T-cell homeostasis.Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV ؉ patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling.Immunophenotypic analysis of T cells from 29 HIV ؊ controls and 43 untreated HIV ؉ patients (30 of whom were followed longitudinally for < 24 months on ART) was performed. Restoration of both CD4 ؉ and CD8 ؉ T cells was driven by increases in CD127 ؉ naive and central memory T cells. CD4 ؉ T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127 ؉ cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance. IntroductionT-cell homeostasis tightly regulates the composition of the T-cell compartment, 1 but many aspects of these homeostatic mechanisms in humans remain unclear. IL-7 is a cytokine produced by stromal cells in the BM, thymus, and lymph node 2 and is critical for T-cell thymopoiesis. Through the JAK-STAT5 signaling pathway, IL-7 is essential for the development, maturation, and survival of naive and memory T cells in the periphery. [2][3][4][5][6] The IL-7 receptor (IL-7R) consists of 2 chains: the ␣ chain (IL-7R␣/CD127) and the common ␥ chain shared by IL-2, IL-4, IL-9, Previous studies have found that, in addition to T cells, dendritic cells and monocytes also express CD127. 8,9 Elevated levels of serum or plasma IL-7 have been observed in CD4 T-cell lymphopenia, including HIV infection, idiopathic CD4 lymphocytopenia, and after chemotherapy and BM transplantation. [10][11][12][13] A strong inverse association has been observed between serum IL-7 levels and CD4 T-cell counts, especially in severe CD4 T-cell lymphopenia (Ͻ 200 cells/L). 10,11 Two possible hypotheses have been proposed to explain this association: increased production of IL-7 as part of a compensatory homeostatic response (possibly regulated by the presence of CD127 receptor on dendritic cells) or decreased receptor-mediated clearance from reduced availability of CD127 in lymphopenic conditions [14][15][16][17] leading to accumulation of IL-7. It has been previously described that CD8 T-cell proliferation is more effective than CD4 proliferation in recovering depleted populations in response to homeostatic signals. 18 Some studies have further suggested that very high IL-7 levels may negatively affect CD4 T-cell homeostatic proliferation, 9 although in other animal models of lymphopenia-induced proliferation, excess IL-7 led to improved restoration of the T-cell pool, des...