Gene expression profiling of interferon-alpha-treated HTLV-1-infected CD4+ T cell lines

Background: Interferon-alpha (IFN-a) contributes extensively to the host immune response upon viral infection through antiviral, pro-apoptotic, antiproliferative and immunomodulatory activities. Although extensively documented in various types of human cancers and viral infections, controversy exists in the exact mechanism of action of IFN-a in human immunodeficiency virus type 1 (HIV-1) and human T lymphotropic virus type 1 (HTLV-1) retroviral infections. Principal Findings: IFN-a displayed robust anti-HIV-1 effects in HTLV-1/HIV-1 co-infected MT-4 cells in vitro, demonstrated by the dose-dependent inhibition of the HIV-1-induced cytopathic effect (IC50 = 83.5IU/ml, p < 0.0001) and p24 secretion (IC50 = 1.2 IU/ml, p < 0.0001). In contrast, IFN-a treatment did not affect cell viability nor HTLV-1 viral RNA levels in HTLV-1 mono-infected cell lines, based on flow cytometry and nCounter analysis. However, we were able to confirm the previously described posttranscriptional inhibition of HTLV-1 p19 secretion by IFN-a, both in cell lines (p = 0.0045) as well as in adult T cell leukemia patient samples (p = 0.031). In addition, through microarray and nCounter analysis, we demonstrated significant transcriptional activation of interferon-stimulated genes and intact IFN-a signaling in HTLV-1-infected cell lines. Conclusions: Taken together, our results indicate that both the absence of in vitro antiproliferative and pro-apoptotic activity, as well as the modest posttranscriptional antiviral activity of IFN-a against HTLV-1, was not due to a cell intrinsic defect in IFN-a signalisation, but rather represents a retrovirus-specific phenomenon, considering the robust HIV-1 inhibition in co-infected cells. The microarray experiment consists of 46 hybridizations in total. For MT-2 cells, triplicate samples (from three independent RNA experiments) were used for untreated (C), IFN-a-, A-, and A+IFN-a-treated cells, duplicate samples for Q2- and Q3-treated cells (from two independent RNA experiments), and one sample for IFN-b-treated cells. For MT-4 cells, quadruplicate samples (from four independent RNA experiments) were used for untreated (C), IFN-a-, A-, and A+IFN-a-treated cells, and duplicate samples for Q2-, Q3-, and IFN-b-treated cells (from two independent RNA experiments). A (AZT) , Q2, and Q3 are drug candidates.