New insights for FOXO and cell-fate decision in HIV infection and HIV associated neurocognitive disorder

Abstract

Human immunodeficiency virus Type 1 (HIV-1) infection and associated diseases continue to represent major health problem worldwide. FOXO transcriptional factors play an important role in the regulation of cell apoptosis, cell cycle arrest, stress resistance, metabolism and differentiation. This chapter will discuss the diverse functions of FOXO in different cell types including T-cells, macrophages, neurons and astrocytes within the context of HIV-1 infection. Given the overwhelming evidence that FOXO proteins influence the cell fate of immune cells and involve in the homeostasis of the central nervous system (CNS), we will also discuss the potential role of FOXO factors in HIV-1-associated neurological disorders.

Fig. 1. Proposed mechanisms for how FOXO affects macrophage function during early and late stage of HIV-1 infection

A. In the early stage of HIV-infection, the binding of HIV-1 or HIV-1 proteins with macrophage cell surface receptors induces intracellular signaling cascades such as Akt-1, ERKs, and NF-κB pathways. Activated Akt-1 and ERKs may inhibit FOXO function by phosphorylation. Subsequently, phosphorylated FOXO translocates to the cytoplasm and facilitates ubiquitination and degradation. As a consequence, inhibitory effect of FOXO to NF-κB was removed, which leads to enhanced NF-κB activation that promote viral replication, cell survival, inflammation and cytokine/chemokines production. B. In the late stage of HIV-infection, it has been suggested that productive HIV-1 infection compromises PI3k/Akt-1 pathway, which lead to the activation of FOXO and translocation of FOXO in the nucleus. Activated FOXO triggers apoptosis pathways through increased expression of apoptotic proteins such as Puma. Activated FOXO can also inhibit NF-κB, preventing its pro-survival function. Dashed line indicates signal attenuation.

Fig. 2. Proposed mechanism for how FOXO influence neurons, astrocytes and neuronal progenitor cell function

In response to oxidative stress or starvation, FOXO–dependent transcription in neurons serves to trigger apoptosis by inducing gene expression of FasL, BcL-6, Bim, etc. In astrocyte, FOXO suppress cell proliferation by inducing cell cycle regulatory proteins cyclin G2, Gadd45a and p27/p21. FOXO also play a crucial role in the homeostatic maintenance of neuronal progenitor cells by coordinating quiescence, stress resistance, and/or terminal differentiation.