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Host-directed therapies that augment host immune effector mechanisms may serve as important adjunctive therapies for tuberculosis treatment. We evaluated the activity of denileukin diftitox in an acute mouse model of tuberculosis (TB) infection and analyzed the cellular composition and bacterial burden in lungs and spleens. These in vivo studies show that denileukin diftitox potentiates standard TB treatment in the mouse model, an effect which may be due to depletion of T-regulatory and myeloid-derived suppressor cells during TB infection. Our results indicate that denileukin diftitox and other suppressor cell-depleting therapies may be useful adjunctive, host-directed therapies for TB. [ABSTRACT FROM AUTHOR]

Background: Sensitive assays are needed for detection of residual human immunodeficiency virus (HIV) in patients with undetectable plasma viral loads to determine whether eradication strategies are effective. The gold standard quantitative viral outgrowth assay (QVOA) underestimates the magnitude of the viral reservoir. We sought to determine whether xenograft of leukocytes from HIV type 1 (HIV)-infected patients with undetectable plasma viral loads into immunocompromised mice would result in viral amplification.Methods: Peripheral blood mononuclear cells or purified CD4(+) T cells from HIV or simian immunodeficiency virus (SIV)-infected subjects with undetectable plasma viral loads were adoptively transferred into NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. The mice were monitored for viremia following depletion of human CD8(+) T cells to minimize antiviral activity. In some cases, humanized mice were also treated with activating anti-CD3 antibody.Results: With this murine viral outgrowth assay (MVOA), we successfully amplified replication-competent HIV or SIV from all subjects tested, including 5 HIV-positive patients receiving suppressive antiretroviral therapy (ART) and 6 elite controllers or suppressors who were maintaining undetectable viral loads without ART, including an elite suppressor from whom we were unable to recover virus by QVOA.Conclusions: Our results suggest that the MVOA has the potential to serve as a powerful tool to identify residual HIV in patients with undetectable viral loads. [ABSTRACT FROM AUTHOR]

Administration of interleukin (IL)-2 to human immunodeficiency virus (HIV)-infected patients leads to significant increases in CD4 T cell counts. We previously have shown that IL-2 induces increased proliferation and survival of CD4 T cells. Deuterium labeling studies were undertaken to study the relationship between IL-2-induced increases in theCD4Tcell count and the effects of IL-2 on cell proliferation and survival.Astrong inverse correlation was noted between the rate of decay of the label in CD4 cells and increases in CD4 cell counts (R = 0.67; P<.001). This correlation was not seen with the level of proliferating cells. Although the CD4 cell count at baseline and the number of CD4 cells expressing CD25 were also predictive of increases in the CD4 cell count, the rate of decay remained the most statistically significant predictor in multivariate regression models. Thus, an increase in the survival of CD4T cells appears to be the critical mechanism leading to sustained increases in the CD4 cell counts of HIV-infected patients receiving intermittent IL-2 therapy. [ABSTRACT FROM AUTHOR]

Strategies to limit life-long dependence on antiretroviral therapy (ART) are needed. We randomized 81 human immunodeficiency virus (HIV)-infected subjects to 4 interventional arms involving continued ART plus ALVAC vCP1452 (or placebo) with or without interleukin (IL)-2 infusions. Viral load rebound 12 weeks after ART interruption was then analyzed to assess immune control. Fifty-two subjects reached the study end point. ALVAC recipients had 0.5 log 10 lower virologic rebounds (P = .033). IL-2 plus vaccine boosted CD4+ T cell counts (P < .001) but did not diminish viral rebound. Significant changes were not detected for HIV-specific lymphoproliferative responses in any arm. This exploratory protocol provides useful clinical data for future therapeutic immunization trial design. [ABSTRACT FROM AUTHOR]

Background: Patients infected with hepatitis C virus (HCV) and human immunodeficiency virus have a diminished HCV virologic response to standard interferon (IFN)-based therapies. We explored the strategy of initial immunostimulatory therapy with interleukin (IL)-2, followed by the addition of specific anti-HCV therapy, as a possible synergistic approach to treatment.Methods: Coinfected subjects (n=23) with CD4 cell counts >300 cells/ micro L received low-dose IL-2 daily for 12 weeks, followed by pegylated IFN- alpha 2b and ribavirin for an additional 48 weeks. The primary end point was permanent discontinuation of treatment before week 24 due to toxicity or intolerance.Results: Six subjects (26.1%) discontinued treatment before week 24, and 11 (47.8%) discontinued treatment before week 60. Overall, 4 subjects discontinued because of adverse events. Four of 23 (17%; 95% confidence interval [CI], 5%-39%) had sustained virologic responses. Of 17 subjects with increased levels of alanine aminotransferase at baseline, 13 had follow-up measurements at week 60, of which 6 (46%) were normal.Conclusions: Low-dose IL-2 plus PEG-IFN and ribavirin was associated with a high discontinuation rate. Although the study was not powered for efficacy, CIs surrounding the treatment response rate suggest that this strategy should not be pursued in larger trials. [ABSTRACT FROM AUTHOR]

Twenty-two patients with CD4[sup +]cell counts ≤200 cells/µL after 12 months of stable highly active antiretroviral therapy (HAART; "immunologic nonresponders") were randomly assigned to receive subcutaneous low-dose prolonged intermittent interleukin (IL)-2 in addition to HAART (n = 12) or to continue HAART alone (n = 10). At 48 weeks of follow-up, no IL-2-related serious adverse events and no significant differences in plasma human immunodeficiency virus (HIV) RNA level were observed in the 2 groups. A higher incidence of HIV-related clinical events was observed among patients receiving HAART alone (3/10) than among subjects receiving HAART plus IL-2 (0/12). Significant increases in CD4[sup +], naive, and CD4[sup +]CD7[sup +] cells and plasma levels of IL-7 were observed in patients receiving IL-2 versus patients receiving HAART alone. A significant increase in cell turnover did not lead to a decrease in the frequency of T cell receptor excision circles, which remained stable. Rather, increased numbers of T cell receptor excision circles per microliter of blood were observed (not statistically significant). Thus, adjuvant IL-2 therapy in immunologic nonresponders resulted in a clinical benefit, suggesting that the quantitative cell recovery involves functionally competent immune cells. [ABSTRACT FROM AUTHOR]

Evaluates the safety and efficacy of three regimens of intermittent subcutaneous interleukin (IL)-2 in antiviral drug-experienced HIV-infected persons with detectable virus load. Impact of IL-2 regimens on circulating CD4 T cells; Plasma viremia; Drug resistance genotyping; Therapy changes and toxicity.

Describes the effects of intermittent interleukin (IL)-2 therapy on HIV through a study of patients undergoing detailed virological evaluation during a year of therapy. Increase in plasma HIV during at least one IL-2 cycle; Absence of changes seen in lymphoid levels of HIV during the period of therapy; Resemblance of a virus induced by IL-2 to pre-IL-2 plasma quasi species.