Novel alpha interferon (IFN-alpha) variant with improved inhibitory activity against hepatitis C virus genotype 1 replication compared to IFN-alpha2b therapy in a subgenomic replicon system.

Hepatitis C virus (HCV) treatment is based on the association of pegylated alpha interferon (IFN-alpha) and ribavirin. To improve the level of sustained virological response to treatment, especially in patients infected with HCV genotype 1, new IFNs with improved efficacy and toxicity profiles may be developed. In this report, we show that, in the BM4-5 cell line harboring an HCV subgenomic replicon, a novel and naturally occurring human IFN-alpha17 variant, GEA007.1, which was discovered by using an original population genetics-based drug discovery approach, inhibits HCV genotype 1 RNA replication more efficiently than does IFN-alpha2b. Moreover, we show that complete viral clearance is obtained in BM4-5 cells after long-term treatment with GEA007.1, while HCV subgenomic RNA is still detected in cells treated with other IFN-alpha variants or with standard IFN-alpha2b. Eventually, we demonstrate that the better inhibitory activity of GEA007.1 compared to that of standard IFN-alpha is likely to be due to stronger and faster activation of the JAK-STAT signaling pathway and to broader expression of IFN-alpha-responsive genes in cells. Our results demonstrate a superior inhibitory activity of GEA007.1 over that of IFN-alpha2b in the HCV replicon system. Clinical trials are required to determine whether GEA007.1 could be a potent "next generation" IFN for the treatment of HCV infection, especially in nonresponders or relapsing patients infected with HCV genotype 1 who currently represent a clinical unmet need.

Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial.

BACKGROUND: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients. METHODS: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550 x 10(6) cells/l were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5 x 10(6) IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74. RESULTS: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262 x 10(6) cells/l, respectively; P < 0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls (P < 0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 (P < 0.0001) and natural killer cells (P < 0.001). In a logistic regression analysis, odds of being responders to recall antigens was 8.5-fold higher in IL-2 recipients (P = 0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P = 0.01). CONCLUSIONS: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone.

Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy.

OBJECTIVE: Combination antiretroviral therapy in a subset of HIV-infected patients, here called CD4-low responders (CD4-LR), fails to produce a rapid rise in CD4 cell counts despite effective control of plasma viral load (< 50 copies/ml). The mechanism responsible for this failure was investigated. DESIGN AND METHODS: CD4-LR patients (n = 13) included in the study had been receiving stable antiretroviral therapy for > 9 months, resulting in undetectable viral load, but nontheless showed a CD4 cell count of < 200 x 106 cells/l. Samples from these patients were analysed for intracellular expression of the anti-apoptotic molecule Bcl-2 and the in vitro apoptosis of their CD4 lymphocytes. Since interleukin-2 (IL-2) induces Bcl-2 and participates in the control of lymphocyte apoptosis, we also investigated the IL-2/IL-2 receptor (IL-2R) system in these CD4-LR patients. All these investigations were performed before and after the CD4-LR patients received IL-2 therapy. RESULTS: CD4 T lymphocytes from these patients underexpressed the anti-apoptotic molecule Bcl-2 and were more susceptible to spontaneous apoptosis. Peripheral CD4 T lymphocytes from the CD4-LR patients showed a regulatory dysfunction in the IL-2R system that resulted in a lack of reactivity to IL-2. Overall, the results obtained with CD4-LR patients differed radically from those in patients undergoing successful antiretroviral therapy. Finally, an increase in Bcl-2 expression and IL-2 reactivity was observed in the CD4 T lymphocytes of CD4-LR patients receiving IL-2 immunotherapy. This correlated with a reduction in their apoptosis. CONCLUSION: Our study characterizes the defective maintenance of peripheral CD4 T lymphocytes in CD4-LR patients, probably resulting from Bcl-2 underexpression and dysregulation of the IL-2R system.