Chronic immune activation and progression to AIDS are observed after SIV infection in macaques but not in natural host primate species. To better understand this dichotomy, we compared acute pathogenic SIV infection in pigtailed macaques (PTs) to non-pathogenic infection in African green monkeys (AGMs). SIVagm-infected PTs, but not SIVagm-infected AGMs, rapidly developed systemic immune activation, marked and selective depletion of IL-17-secreting (Th17) cells, and loss of the balance between Th17 and T regulatory (Treg) cells in blood, lymphoid organs, and mucosal tissue. The loss of Th17 cells was found to be predictive of systemic and sustained T cell activation. Collectively, these data indicate that loss of the Th17 to Treg balance is related to SIV disease progression.

In the quest for a functional cure or eradication of HIV infection, we need to know how large the reservoirs are from which infection rebounds when treatment is interrupted. To that end, we quantified SIV and HIV tissue burdens in tissues of infected non-human primates and lymphoid tissue (LT) biopsies from infected humans. Before antiretroviral therapy (ART), LTs harbor more than 98 percent of the SIV RNA+ and DNA+ cells. While ART substantially reduced their numbers, vRNA+ cells were still detectable and their persistence was associated with relatively low drug concentrations in LT compared to peripheral blood. Prolonged ART also reduced the level of SIV and HIV-DNA+ cells, but the estimated size of the residual tissue burden of 108 vDNA+ cells that potentially harbor replication competent proviruses, along with the evidence for continuing virus production in LT despite ART, identify two important sources for rebound following treatment interruption. The large sizes of these tissue reservoirs underscore the challenges in developing “HIV cure” strategies that target multiple sources of virus production.

Cell cycle entry is commonly considered to positively regulate HIV-1 infection of CD4 T cells, raising the question as to how quiescent lymphocytes, representing a large portion of the viral reservoir, are infected in vivo. Factors such as the homeostatic cytokine IL-7 have been shown to render quiescent T cells permissive to HIV-1 infection, presumably by transiently stimulating their entry into the cell cycle. However, we show here that at physiological oxygen (O 2 ) levels (2–5% O 2 tension in lymphoid organs), IL-7 stimulation generates an environment permissive to HIV-1 infection, despite a significantly attenuated level of cell cycle entry. We identify the IL-7–induced increase in Glut1 expression, resulting in augmented glucose uptake, as a key factor in rendering these T lymphocytes susceptible to HIV-1 infection. HIV-1 infection of human T cells is abrogated either by impairment of Glut1 signal transduction or by siRNA-mediated Glut1 down-regulation. Consistent with this, we show that the susceptibility of human thymocyte subsets to HIV-1 infection correlates with Glut1 expression; single-round infection is markedly higher in the Glut1-expressing double-positive thymocyte population than in any of the Glut1-negative subsets. Thus, our studies reveal the Glut1-mediated metabolic pathway as a critical regulator of HIV-1 infection in human CD4 T cells and thymocytes.

The IL-7 cytokine promotes the survival of a diverse T-cell pool, thereby ensuring an efficient immune response. Moreover, IL-7 induces the proliferation of recent thymic emigrants (RTEs) in neonates. Here, we demonstrate that the survival and proliferative effects of IL-7 on human RTEs can be distinguished on the basis of dose as well as duration of IL-7 administration. A dose of 0.1 ng/mL IL-7 is sufficient to promote viability, whereas cell-cycle entry is observed only at doses higher than 1 ng/mL. Moreover, a short 1-hour exposure to high-dose IL-7 (10 ng/mL) induces long-term survival but continuous IL-7 exposure is necessary for optimal cell-cycle entry and proliferation. We find that distinct signaling intermediates are activated under conditions of IL-7-induced survival and proliferation; STAT5 tyrosine phosphorylation does not correlate with proliferation, whereas up-regulation of the glucose transporter Glut-1 as well as increased glucose uptake are markers of IL-7-induced cell cycle entry. Glut-1 is directly regulated by PI3K and, indeed, inhibiting PI3K activity abrogates IL-7-induced proliferation. Our finding that the survival and proliferation of RTEs are differentially modulated by the dose and kinetics of exogenous IL-7 has important implications for the clinical use of this cytokine. IntroductionThe IL-7 cytokine is essential for early T-cell development and proliferation 1,2 and plays a role in peripheral T-cell survival and expansion. 3 In contrast to cytokines such as IL-2, which may be restricted by the expression profile of their receptors, IL-7 is likely to have widespread effects due to receptor expression on the vast majority of peripheral T lymphocytes. The IL-7R is composed of a 75-kDa IL-7R␣ subunit that is associated with the IL-2R common ␥ chain (␥ c ). 4 Under conditions of lymphopenia, IL-7 supports the homeostatic proliferation of peripheral T lymphocytes, promoting the expansion of T cells with a diverse T-cell receptor (TCR) repertoire. [5][6][7][8] Exogenous IL-7 therapy can enhance these effects, promoting thymic expansion and short-term proliferation of peripheral T cells. 5,[8][9][10][11][12][13][14][15] The ensemble of these properties has lead to the possibility that recombinant IL-7 be used as an adjuvant immune therapy, improving T-cell reconstitution in lymphopenic patients as well as augmenting vaccine responses. Indeed, exciting preliminary work assessing the effects of IL-7 in patients has recently been published, demonstrating transient increases in peripheral CD4 ϩ as well as CD8 ϩ T cells. 16 These findings are consistent with preclinical primate studies showing that exogenous IL-7 results in significant increases in cell-cycle entry of T lymphocytes. 13,15,17 As observed in these primate studies, the effects of IL-7 in humans were transient, with proliferation and T-cell counts returning to baseline within a short period after cessation of cytokine therapy.Recent thymic emigrants (RTEs) show increased proliferation to IL-7 compared with long-term resident peri...