Simultaneous RNA quantification of human and retroviral genomes reveals intact interferon signaling in HTLV-1-infected CD4+ T cell lines.
BACKGROUND
IFN-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.


RESULTS
IFN-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.


CONCLUSIONS
Taken 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.
Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, KULeuven, Leuven, Belgium.
Britta
B
Moens
Christophe
C
Pannecouque
Giovanni
G
López
Michael
M
Talledo
Eduardo
E
Gotuzzo
Ricardo
R
Khouri
Achiléa
A
Bittencourt
Lourdes
L
Farré
Bernardo
B
Galvão-Castro
Anne-Mieke
AM
Vandamme
Johan
J
Van Weyenbergh
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002470:Cell Survival; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction
D016898:Interferon-alpha; D012313:RNA