Abstract
BackgroundIFN-α contributes extensively to 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-α in human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) retroviral infections.ResultsIFN-α displayed strong anti-HIV-1 effects in HIV-1/HTLV-1 co-infected MT-4 cells in vitro, demonstrated by the dose-dependent inhibition of the HIV-1-induced cytopathic effect (IC50 = 83.5 IU/ml, p < 0.0001) and p24 levels in cell-free supernatant (IC50 = 1.2 IU/ml, p < 0.0001). In contrast, IFN-α treatment did not affect cell viability or HTLV-1 viral mRNA levels in HTLV-1 mono-infected cell lines, based on flow cytometry and nCounter analysis, respectively. However, we were able to confirm the previously described post-transcriptional inhibition of HTLV-1 p19 secretion by IFN-α in cell lines (p = 0.0045), and extend this finding to primary Adult T cell Leukemia patient samples (p = 0.031). In addition, through microarray and nCounter analysis, we performed the first genome-wide simultaneous quantification of complete human and retroviral transciptomes, demonstrating significant transcriptional activation of interferon-stimulated genes without concomitant decrease of HTLV-1 mRNA levels.ConclusionsTaken together, our results indicate that both the absence of in vitro antiproliferative and pro-apoptotic activity as well as the modest post-transcriptional antiviral activity of IFN-α against HTLV-1, were not due to a cell-intrinsic defect in IFN-α signalisation, but rather represents a retrovirus-specific phenomenon, considering the strong HIV-1 inhibition in co-infected cells.
Highlights
IFN-α contributes extensively to host immune response upon viral infection through antiviral, proapoptotic, antiproliferative and immunomodulatory activities
We demonstrate that IFN-α exerts pronounced anti-human immunodeficiency virus type 1 (HIV-1) effects in human T-lymphotropic virus type 1 (HTLV-1) coinfected cells, but has a limited, post-transcriptional, antiviral effect upon HTLV-1 in mono-infected cells
IFN-α selectively affects cell viability of HIV-1/HTLV-1 coinfected but not HTLV-1 mono-infected cells To assess the effects of IFN-α on cell viability of HTLV1-infected cell lines, we quantified pro-apoptotic and proliferation-associated (PCNA) markers via flow cytometry after IFN-α treatment (10 - 103 IU/ml) at different time points
Summary
IFN-α contributes extensively to host immune response upon viral infection through antiviral, proapoptotic, antiproliferative and immunomodulatory activities. Extensively documented in various types of human cancers and viral infections, controversy exists in the exact mechanism of action of IFN-α in human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) retroviral infections. 33 million people are estimated to be infected with HIV-1 and 10 to 30 million people with HTLV-1 [1,2]. Both retroviruses share similarities in TSP), albeit in a minority of infected individuals [1,4,5]. Consensus guidelines for HAM/TSP treatment are missing due to the lack of randomized controlled clinical trials
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