Abstract
HIV-1 Nef protein has key roles at almost all stages of the viral life cycle. We assessed the role of the Nef/eEF1A (eukaryotic translation elongation factor 1-alpha) complex in nucleocytoplasmic shuttling in primary human macrophages. Nuclear retention experiments and inhibition of the exportin-t (Exp-t) pathway suggested that cytoplasmic relocalization of eEF1A, mediated by Exp-t, occurs in Nef-treated monocyte-derived macrophages (MDMs). We observed the presence of tRNA in the Nef/eEF1A complexes. Nucleocytoplasmic relocalization of the Nef/eEF1A complexes prevented stress-induced apoptosis of MDMs treated with brefeldin-A. Blockade of stress-induced apoptosis of MDMs treated with HIV-1 Nef resulted from enhanced nucleocytoplasmic transport of eEF1A with decreased release of mitochondrial cytochrome c, and from increased tRNA binding to cytochrome c, ultimately leading to an inhibition of caspase activation. Our results indicate that HIV-1 Nef, through the nucleocytoplasmic relocalization of eEF1A and tRNAs, enhances resistance to stress-induced apoptosis in primary human macrophages.
Highlights
Excessive reactive oxygen species (ROS) production not appropriately compensated by antioxidant molecules can lead to oxidative stress, which may have an important role in pathogenesis of HIV infection through various mechanisms.[3,4,5] In monocytes from asymptomatic patients, the levels of Bcl-2 and thioredoxin (TRX) decrease,[4] which is associated with enhanced hydrogen peroxide production, whereas in cells from AIDS patients the levels returned to normal.[6]
Nuclear-cytoplasmic relocalization of recombinant Nef (rNef)/Eukaryotic translation elongation factor 1-alpha (eEF1A)/ tRNA complexes prevented stress-induced apoptosis of monocyte-derived macrophages (MDMs) treated with BFA through decreased release of mitochondrial cytochrome c, enhanced tRNA binding to released cytosolic cytochrome c and increased cytoplasmic levels of eEF1A, resulting in decreased caspase activation (Figure 7)
Our results indicate that the HIV-1 Nef protein enhances resistance to stress-induced apoptosis in MDMs through the nuclear-cytoplasmic relocalization of rNef/ eEF1A/tRNA complexes
Summary
Excessive ROS production not appropriately compensated by antioxidant molecules can lead to oxidative stress, which may have an important role in pathogenesis of HIV infection through various mechanisms.[3,4,5] In monocytes from asymptomatic patients, the levels of Bcl-2 and thioredoxin (TRX) decrease,[4] which is associated with enhanced hydrogen peroxide production, whereas in cells from AIDS patients the levels returned to normal.[6]. Nef a 27-kDa HIV-1 protein is translated from multiply spliced viral mRNAs early during infection.[16] Endogenous Nef may have evolved a number of different, independent functional activities to enhance the replication and survival of the virus within infected cells and to facilitate its spread in vivo.[17] Nef enhances virion infectivity and increases viral replication in primary lymphocytes and macrophages.[18] The protein can mediate downregulation of CD4 cell surface expression, a phenomenon important for the release of HIV-1 from the cell.[17] In addition, Nef can downregulate the cell surface expression of major histocompatibility complex class I molecules, an effect found to protect infected cells from cytotoxic T cells.[19] The Nef protein prevents apoptosis of HIV-
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