HIV-1-Mediated Suppression of IFN- Production Is Associated with Inhibition of IRF-7 Translocation and PI3K/akt Pathway in Plasmacytoid Dendritic Cells

Interferon- (IFN-) 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- 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- production by pDCs using the primary pDCs were explored. The nuclear translocation of the interferon regulatory factor (IRF)-7, a transcription factor for IFN- genes, is essential for the initiation of IFN- 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- suppression. The findings suggest that HIV-1 may alter AKT phosphorylation to inhibit the translocation of IRF-7 into pDC nucleus, leading to IFN- suppression, and this may be the reason for IFN- abrogation observed in recently infected HIV patients. Understanding of interactions between HIV-1 and signaling pathways leading to IFN- secretion may provide targets for immune intervention.