UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a novel mechanism, involving up-regulation of the interleukin (IL)-7 cytokine receptor, by which human immunodeficiency virus (HIV) enhances its own production in monocyte-derived macrophages (MDM) in vitro. HIV-1 infection or treatment of MDM cultures with exogenous HIV-1 Tat(86) protein up-regulates the IL-7 receptor (IL-7R) alpha-chain at the levels of steady-state RNA, protein, and functional IL-7R on the cell surface (as measured by ligand-induced receptor signaling). This IL-7R up-regulation is associated with increased amounts of HIV-1 virions in the supernatants of infected MDM cultures treated with exogenous IL-7 cytokine. The overall effect of IL-7 stimulation on HIV replication in MDM culture supernatants is typically in the range of one log and greater. The results are consistent with a model in which HIV infection produces the Tat protein, which in turn up-regulates IL-7R in a paracrine manner. This results in increased IL-7R signaling in response to the IL-7 cytokine, which ultimately promotes early events in HIV replication, including binding/entry and possibly other steps prior to reverse transcription. The results suggest that the effects of IL-7 on HIV replication in MDM should be considered when analyzing and designing clinical trials involving treatment of patients with IL-7 or Tat vaccines.
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PMID:HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro. 1661 57

Studies on thymopoiesis are critical to the understanding of T-cell homeostasis as well as the host response to T-cell depletion. Various in vitro culture systems have been used in the study of thymocyte development; however it is unclear if current co-culture methods have been fully optimized. In this study in vitro suspension cultures have been re-evaluated and the optimal storage conditions for thymocytes have been established by evaluating various methods of storing/isolating thymic tissue and isolated thymocytes as well as the source of thymic epithelial cells (TEC). It was determined that thymocytes must be freshly isolated from whole thymic tissue and ideally stored at 4 degrees C prior to co-culture. Co-culture with either autologous or allogeneic TEC results in similar thymocyte subset distribution as well as interleukin-7 receptor-alpha (CD127) expression on these subsets. To evaluate the influence of the source of TEC on one aspect of thymocyte function the effect of IL-7 stimulation on the expression of CD127 was evaluated. IL-7 stimulation resulted in a downregulation of the expression of CD127 on all thymic subsets similar to that observed in circulating CD8+ T-cells. The effect of this was the same whether TEC were autologous or allogeneic. Optimizing culture techniques and facilitating the study of individual thymocyte subsets will lead to a better understanding of thymic function and development. It could also lead to therapeutic approaches that enhance immune recovery after T-cell depletion in HIV infection, bone marrow transplantation or following chemotherapy.
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PMID:Optimization of culture and storage conditions for an in vitro system to evaluate thymocyte phenotype and function. 1664 13

HIV infection selectively targets CD4+ effector memory T (T EM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the T EM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ T EM cells with little effect on the naive or central memory T (T CM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. T EM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ T EM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4 + T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.
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PMID:IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates. 1669 Dec 94

Despite an increase in plasma IL-7 levels, the CD4 T-cell pool decrease progressively in HIV-infected patients. Here we report on our tests to check the hypothesis that defects in the IL-7 receptor system might be involved in this phenomenon. The cell surface expression of CD127 was measured ex vivo in CD4 and CD8 T lymphocytes drawn from 3 groups of HIV patients. IL-7 function was also followed in vitro by measuring IL-7-driven T-cell proliferation, the induction of the CD25 activation marker, and overexpression of the antiapoptotic molecule Bcl-2. Untreated viremic patients showed a slight but significant decrease in CD127 expression on the surface of their CD4 lymphocytes. By contrast, CD127 expression was substantially altered on the surface of CD8 T lymphocytes taken from untreated viremic patients. IL-7-induced overexpression of the antiapoptotic molecule Bcl-2 was dramatically altered in viremic patients, whereas IL-7-dependent CD25 induction and T-cell proliferation were reduced. Highly active antiretroviral therapy partially corrected these defects in patients with an undetectable viral load and CD4 counts of more than 400 cells/microL. The effects of HAART were less pronounced in patients with undetectable VL but low CD4 counts (<250 cells/microL). The IL-7 receptor is dysfunctional in the CD4 and CD8 lymphocytes of HIV-infected patients. This may be due to abnormal activation of the immune system in HIV-infected patients and may contribute to the reduced CD4 count and the altered function of the CD8 compartment.
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PMID:Regulatory dysfunction of the interleukin-7 receptor in CD4 and CD8 lymphocytes from HIV-infected patients--effects of antiretroviral therapy. 1681 Jan 23

HAART in HIV-1-infected individuals has a broad spectrum of clinical outcomes. In the majority of patients, plasma viral load becomes undetectable and CD4+ T-cells increase over time. However, in a number of subjects a discrepancy between plasma viral load and the CD4+ T-cell recovery is observed. CD4+ T-cell count can rise despite persistently detectable plasma viral load (virologic nonresponders), or conversely does not increase despite full plasma viral load suppression (immunologic nonresponder). Defective immune reconstitution may depend on several factors including previous therapeutic failure, duration of antiretroviral therapy, low CD4+ T-cell count at the initiation of HAART, advanced stage of disease, low adherence to HAART, and previous treatment interruption. There is no definitive evidence that age, viral strain/clade, or host genetic factors play a role in these different responses to HAART. The roles of T-cell subsets, thymic function, and cytokines have been investigated. The increased T-cell activation/apoptosis has been associated with a lack of effective immunologic response. Unabated virologic replication in lymphoid tissues, despite undetectable plasma viral load, has been proposed as the underlying mechanism of cellular activation. However, this "paradoxical response" probably can be associated with other events. Insufficient CD4+ T-cell repopulation of lymphoid tissues may be due to a thymus failure or a defect in bone marrow function. Lifelong infection, the toxic effect of antiviral drugs on T- and B-cell precursors, the stage of disease, and the low number of CD4+ T-cells before HAART may also account for thymus exhaustion and insufficient T-cell renewal. Finally, an imbalance in the production of cytokines such as TNF, IL-2 and IL-7 may also be a crucial event for the induction of immune system failure. In patients in which CD4+ T-cells are not increased by HAART, therapeutic strategies aimed at increasing these cells and reducing the risk of infections are needed. IL-2 and/or other cytokines may be of benefit in this setting. Some antiviral drugs may be better than others in immunologic reconstitution. Protease inhibitors may have additional, independent positive effects on the immune system. On the other hand, there may be little rationale for using immunosuppressive agents such as cyclosporine or hydroxyurea in this subgroup of immunologic nonresponder patients, as these molecules may increase T-cell decline and/or favor susceptibility to infections.
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PMID:Failure to reconstitute CD4+ T-cells despite suppression of HIV replication under HAART. 1684 76

Acute HIV/SIV (human/simian immunodeficiency virus) infection results in severe CD4(+) T cell depletion in lymphoid compartments. During the chronic phase of infection, CD4(+) T cell numbers rebound in blood but remain low in the gut-associated lymphoid tissue (GALT), even when viral replication is suppressed by antiretroviral therapy (ART). Thus, strategies to repopulate lymphoid compartments may ameliorate the clinical outcome of HIV/SIV infection. Interleukin (IL)-7 is a key cytokine for the maintenance of homeostatic proliferation of T cells. In HIV/SIV infection, IL-7 expression is increased, likely to compensate for T cell loss, suggesting that supraphysiological administration of IL-7 could provide additional benefit. However, the ability of T cells to respond to IL-7 is dependent on the level of expression of the IL-7 receptor (IL-7R) in T cells in various body compartments. In here, we investigated the proportion of IL-7R(+) T cells in blood, spleen, gut, and genitourinary tract of healthy and SIV-infected macaques with various degrees of CD4(+) T cell depletion. We found that the percentage of T cells expressing IL-7R was significantly lower in both CD4(+) and CD8(+) T cell subsets in SIV-infected macaques than in healthy animals and this decrease directly correlated with the CD4(+) T cell number. Importantly, the proportion of CD4(+) and CD8(+) T cells expressing IL-7R in blood paralleled that found in tissues. IL-7R(+) T cells within the SIV-specific CD8(+) T cells varied and were lowest in most tissues of viremic macaques, likely reflecting continuous antigen stimulation of effector cells.
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PMID:Decreased number of CD4+ and CD8+ T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques. 1693 9

The theoretical objectives of cytokine therapies in HIV infection are to impact T cell homeostasis and/or to improve immune functions or the mobilization of the HIV reservoir. Among cytokines, IL-2 and IL-7 are promising agents under clinical evaluation. Intermittent administration of IL-2 is by far the furthest studied strategy in HIV infection. This cytokine increases CD4 T lymphocytes in HIV-infected individuals. Recent clinical data showed that this effect is sustained over years. IL-2 therapy induces a peripheral expansion of T cells as a consequence of prolonged survival of T cells and decreased immune activation. These effects suggest that a cytokine therapy may interfere with critical factors of HIV disease. Recent data provide arguments that IL-2 therapy improves immune functions in HIV-infected patients. Whether these effects may be translated into clinical benefits is under evaluation in ongoing phase III studies. The potential interest of IL-7 in the treatment of HIV-infection is based on its crucial role on T cell homeostasis both in thymic output and peripheral T proliferation and survival. Although no data in human are still available, recent studies provide arguments to assess this cytokine in HIV infection. Phase I studies are ongoing or planned.
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PMID:[Cytokine therapies in HIV infection]. 1696 51

We have previously shown decreased expression of the interleukin (IL)-7 receptor alpha-chain (CD127) on CD8 T-cells in HIV-infected patients and an apparent recovery of this receptor in those receiving antiretroviral therapy with sustained viral suppression. Here, we demonstrate that the HIV Tat protein specifically downregulates cell surface expression of CD127 on human CD8 T-cells in a dose- and time-dependent manner. The effects of Tat on CD127 expression could be blocked with anti-Tat monoclonal antibodies or by preincubating Tat with heparin. Tat had no effect on the expression of other cell surface proteins examined, including CD132, or on cell viability over 72 hours. Further, CD127 expression was not altered by other HIV proteins, including gp160 or Nef. Preincubation of purified CD8 T-cells with Tat protein inhibited CD8 T-cell proliferation and perforin synthesis after stimulation with IL-7. Because IL-7 signaling is essential for optimal CD8 T-cell proliferation and function, the downregulation of CD127 and apparent inhibition of cytotoxic activity by Tat may play an important role in HIV-induced immune dysregulation and impaired cell-mediated immunity.
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PMID:Interleukin-7 receptor expression on CD8 T-cells is downregulated by the HIV Tat protein. 1696 44

During antiretroviral therapy, CD4 lymphocyte count increases are modest in some patients despite virologic control. We explored whether polymorphisms in genes important for T cell expansion, survival, and apoptosis are associated with the magnitude of CD4 lymphocyte count recovery during antiretroviral therapy. We studied treatment-naive individuals who achieved sustained control of plasma viremia (<400 HIV-1 RNA copies/mL) for at least 48 weeks after initiation of antiretroviral therapy and compared genotypes among individuals who had an increase of either <200 or > or =200 CD4 cells/mm3 from baseline. A total of 137 single-nucleotide polymorphisms across 17 genes were characterized in 873 study participants. In multivariate analyses that controlled for clinical variables, polymorphisms in genes encoding tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), TNF- alpha , Bcl-2-interacting molecule (Bim), interleukin (IL)-15, and IL-15 receptor alpha chain (IL-15R alpha ) were associated with the magnitude of the increase in CD4 lymphocyte count, as were haplotypes in genes encoding interferon- alpha , IL-2, and IL-15R alpha (P < .05, for each). Multifactor dimensionality reduction identified a gene-gene interaction between IL-2/IL-15 receptor common beta chain and IL-2/IL-7/IL-15 receptor common gamma chain. Immune recovery during antiretroviral therapy is a complex phenotype that is influenced by multiple genetic variants. Future studies should validate these tentative associations and define underlying mechanisms.
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PMID:Immunogenetics of CD4 lymphocyte count recovery during antiretroviral therapy: An AIDS Clinical Trials Group study. 1699 Oct 84

CD8+ CD57+ T lymphocytes, present at low levels in the peripheral blood of healthy individuals expand during HIV infection and remain elevated during chronic infection. Their role in the immune response remains unclear. We performed a large-scale gene array analysis (3158 genes) to characterize them and, interestingly, found no distinction in the transcriptional profiles of CD8+ CD57+ T lymphocytes from HIV-infected and uninfected subjects. In both groups, these cells showed specificity for multiple Ags and produced large amounts of IFN-gamma and TNF-alpha. The transcriptional profiles of CD8+ CD57+ and CD8+ CD57- cells, however, differed substantially. We propose that CD8+ CD57+ cells were Ag-driven effector cells with very high cytotoxic effector potential including perforin, granzymes, and granulysin, regardless of HIV status. At both the messenger and protein levels, they expressed more adhesion molecules and fewer chemokine receptors (CCR7 and CXCR4) than CD8+ CD57- cells but expressed preferentially CX3CR1. The lower expression level of genes involved in cell cycle regulation showed limited proliferation capacities of CD8+ CD57+ even in response to TCR and IL-2, IL-7, and IL-15 stimulation. CD8+ CD57+ T cells from both HIV and uninfected subjects maintain effective cytotoxic potentials but are destined to migrate to nonlymphoid tissues without further cycling.
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PMID:High cytotoxic and specific migratory potencies of senescent CD8+ CD57+ cells in HIV-infected and uninfected individuals. 1701 99

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