HIV-1-mediated suppression of IFN-α production is associated with inhibition of IRF-7 translocation and PI3K/akt pathway in plasmacytoid dendritic cells

AS Dhamanage, MR Thakar… - AIDS Research and …, 2019 - liebertpub.com
AS Dhamanage, MR Thakar, RS Paranjape
AIDS Research and Human Retroviruses, 2019liebertpub.com
Abstract Interferon-α (IFN-α) plays a vital role in combating viral infections especially in the
early control after infection. However, the HIV infection has shown substantial level of
suppression of IFN-α secretion during initial phase of infection. The reasons behind this
impairment are still obscure. As plasmacytoid dendritic cells (pDCs) are the major producers
of this cytokine, the mechanisms of HIV-1-mediated suppression of IFN-α production by
pDCs using the primary pDCs were explored. The nuclear translocation of the interferon …
Abstract
Interferon-α (IFN-α) plays a vital role in combating viral infections especially in the early control after infection. However, the HIV infection has shown substantial level of suppression of IFN-α secretion during initial phase of infection. The reasons behind this impairment are still obscure. As plasmacytoid dendritic cells (pDCs) are the major producers of this cytokine, the mechanisms of HIV-1-mediated suppression of IFN-α production by pDCs using the primary pDCs were explored. The nuclear translocation of the interferon regulatory factor (IRF)-7, a transcription factor for IFN-α genes, is essential for the initiation of IFN-α production in pDCs. The HIV-1-exposed pDCs did not show the translocation of IRF-7 into the nucleus in our experiments. Furthermore, it was also observed that HIV-1 inhibited AKT phosphorylation of PI3K/akt pathway in pDCs, an important step for IRF-7 translocation to nucleus. HIV-1-induced inhibition of AKT phosphorylation and IRF-7 translocation was evident even in the presence of Toll-like receptor-7 agonist stimulation and correlated with IFN-α suppression. The findings suggest that HIV-1 may alter AKT phosphorylation to inhibit the translocation of IRF-7 into pDC nucleus, leading to IFN-α suppression, and this may be the reason for IFN-α abrogation observed in recently infected HIV patients. Understanding of interactions between HIV-1 and signaling pathways leading to IFN-α secretion may provide targets for immune intervention.
Mary Ann Liebert