ADAR1 enhances HTLV-1 and HTLV-2 replication through inhibition of PKR activity

Abstract

BackgroundThe role of innate immunity in general and of type I interferon (IFN-I) in particular in HTLV-1 pathogenesis is still a matter of debate. ADAR1-p150 is an Interferon Stimulated Gene (ISG) induced by IFN-I that can edit viral RNAs. We therefore investigated whether it could play the role of an anti-HTLV factor.ResultsWe demonstrate here that ADAR1 is also expressed in the absence of IFN stimulation in activated primary T-lymphocytes that are the natural target of this virus and in HTLV-1 or HTLV-2 chronically infected T-cells. ADAR1 expression is also increased in primary lymphocytes obtained from HTLV-1 infected individuals. We show that ADAR1 enhances HTLV-1 and HTLV-2 infection in T-lymphocytes and that this proviral effect is independent from its editing activity. ADAR1 expression suppresses IFN-α inhibitory effect on HTLV-1 and HTLV-2 and acts through the repression of PKR phosphorylation.DiscussionThis study demonstrates that two interferon stimulated genes, i.e. PKR and ADAR1 have opposite effects on HTLV replication in vivo. The balanced expression of those proteins could determine the fate of the viral cycle in the course of infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-014-0093-9) contains supplementary material, which is available to authorized users.

Current views on interferon therapy for HIV

“…On the other hand, IFN-alpha has been reported to restrict other in vitro retroviral infections, such as human HTLV types 1 and 2 [48,49]. HTLV-2 infection is frequently present in European injecting drug users coinfected with HIV [50][51][52].…”

Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases

“…In HIV-1/tuberculosis co-infected patients, viral infection induced ADAR1 to edit the RNA transcript of the HIV-1 envelope glycoprotein, possibly targeting the HIV-1 RNA for degradation [56]. In human primary CD4+ T cells, however, the increased expressions of both ADAR1 isoforms were concurrent with an enhanced HIV-1 viral replication [57], due to augmented viral protein synthesis [58] (Figure 2). This was attributed first to the increased expression of the p24 Gag protein [59].…”

“…ADAR1p150, produced in response to viral infections, inhibits PKR activation by blocking phosphorylation [62] (Figure 2). This inhibition was observed in measles virus [63], vesicular stomatitis virus [22], human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2) [57], and HIV-1 [60]. The antagonization of PKR activation by ADAR1 requires its dsRNA binding function, but not necessarily its editing function [57].…”

“…This inhibition was observed in measles virus [63], vesicular stomatitis virus [22], human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2) [57], and HIV-1 [60]. The antagonization of PKR activation by ADAR1 requires its dsRNA binding function, but not necessarily its editing function [57]. In these cases, the interferon-inducible ADAR1p150 seems to disrupt the interferon response [57,63,64].…”

“…The antagonization of PKR activation by ADAR1 requires its dsRNA binding function, but not necessarily its editing function [57]. In these cases, the interferon-inducible ADAR1p150 seems to disrupt the interferon response [57,63,64]. …”