HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-XL Expression in an Extracellular Signal-regulated Kinase-dependent Manner

Hyun-Jung Choi,Thomas E Smithgall

doi:10.1074/jbc.m410068200

Hyun-Jung Choi, Thomas E Smithgall

Open Access

https://doi.org/10.1074/jbc.m410068200

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Abstract

The Nef protein of human immunodeficiency virus-1 (HIV-1) is essential for the progression from human and simian immunodeficiency virus infection to full-blown AIDS. Recent studies indicate that Nef generates anti-apoptotic signals in HIV-infected T cells, suppressing cell death early in infection to allow productive viral replication. Previous work from our laboratory has shown that Nef also promotes proliferation of myeloid cells through a signal transducer and activator of transcription 3-dependent pathway. Here we demonstrate that Nef suppresses cell death induced by cytokine deprivation in the human macrophage precursor cell line, TF-1. Nef selectively induced up-regulation of Bcl-XL, an anti-apoptotic gene that is also regulated by granulocyte/macrophage-colony stimulating factor in this cell line. Activation of the extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase pathway also correlated with the survival of TF-1/Nef cells. Using the selective mitogen-activated protein kinase kinase inhibitor PD98059, we found that Nef-induced Erk signaling is essential for Bcl-XL up-regulation and cell survival. In contrast, expression of Bcl-XL and TF-1 survival was not affected by dominant-negative signal transducer and activator of transcription 3. These data suggest that Nef produces survival signals in myeloid cells through Erk-mediated Bcl-XL induction, a pathway distinct from Nef survival pathways recently reported in T lymphocytes.

Highlights

Recent development of a transgenic mouse model for AIDS demonstrated that expression of Nef alone is sufficient to cause AIDS-like pathology [6, 7]
human immunodeficiency virus-1 (HIV-1) Nef Inhibits Apoptosis Induced by Cytokine Deprivation in the Human Myeloid Leukemia Cell Line, TF-1—Previous work from our laboratory has shown that human immunodeficiency viruses (HIV)-1 Nef induces cytokine-independent proliferation of the human macrophage precursor cell line, TF-1 [14]
To investigate whether the GMCSF-independent proliferation induced by Nef results from suppression of apoptosis in TF-1 cells, we first expressed HIV-1 Nef in TF-1 cells by retroviral transduction

Summary

Introduction

Recent development of a transgenic mouse model for AIDS demonstrated that expression of Nef alone is sufficient to cause AIDS-like pathology [6, 7]. Erk is involved in induction of the activator protein-1 (AP-1) transcription factor by Nef in macrophages, another major target cell for HIV infection [11]. Nef suppresses T-cell apoptosis initiated by serum starvation or HIV replication In this case, Nef was shown to induce serine phosphorylation of Bad, the mitochondrial pro-apoptotic mediator, through a previously described p21-activated protein kinase known to associate with Nef [13]. Ative Stat did not impact Nef-induced cell survival or Bcl-XL induction, despite the identification of Bcl-XL as a Stat target gene in other systems [16, 17] These results show, for the first time, that Nef generates anti-apoptotic signals in cells of the myelomonocytic lineage, through a pathway distinct from that observed in T cells

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