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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34870 | GEO | 2015/01/01

SECONDARY ACCESSION(S): PRJNA150111

REPOSITORIES: GEO

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Project description:HIV is able to outpace the innate immune response, including the response mediated by interferon (IFN), to establish a productive infection. However, monocyte derived macrophages (MDMs) may be protected from HIV infection by treatment with type I IFN before virus exposure. The ability of HIV to modulate the type I IFN-mediated innate immune response when it encounters a cell that has already been exposed to IFN was investigated. To investigate the presence of HIV on an established IFN response, MDMs were subjected to four different conditions: (1) IFN-treated only, (2) IFN-treated followed by HIV infection, (3) HIV infected only, and (4) a mock-treated and mock-infected control. Microarray gene expression analysis was performed on a total of 24 samples derived from the 4 conditions assessed at 3 time points (1, 4 and 8 days following treatment/infection) for both IFN-α2 or -ω. Initially, ISGs were identified as those that were upregulated greater than 2-fold by IFN alone (condition 1) at both Days 4 and 8. Then, the IFN-treated condition was compared to the IFN-treated followed by HIV-infection condition in order to identify those ISGs that were downregulated at least 1.5-fold by the presence of HIV at both days. Assuming that it would be counterproductive for HIV infection by itself to induce the expression of ISGs with putative anti-HIV effects, those ISGs that were upregulated greater than 2-fold in the HIV control were removed. Finally, ISGs that passed these filters and were concordant with both IFN-treatments (IFN-α2 and -ω) were identified and corresponded to the following 8 ISGs: AXL receptor tyrosine kinase (AXL), interferon-alpha inducible protein 27 (IFI27), interferon-induced protein 44 (IFI44), interferon-induced protein 44-like (IFI44L), ISG15, OAS1, OAS3 and XIAP associated factor 1 (XAF1). It should be noted that the IFN-α2 and -ω microarray experiments were performed in different batches but batch effects were not corrected since genes were identified by the filtering approach just described within each batch.

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

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