Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis.

Huaqian Dong,Jun Wang,Jinhong Xu,Xiang Ye,Li Zhong,Yiming Shao,Huiqin Xing,Jinhua Qiu

doi:10.3389/fnins.2019.00044

Abstract

There are numerous types of pathological changes in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), including apoptosis of neurons. HIV-1 transactivator of transcription (Tat) protein, which is encoded by HIV-1, may promote apoptosis in HAND. Forkhead box O3 (FOXO3) is a multispecific transcription factor that has roles in many biological processes, including cellular apoptosis. The aim of this study was to determine whether FOXO3 is activated by HIV-1 Tat and to investigate its role in neuronal apoptosis in HAND. We employed tissue staining and related molecular biological experimental methods to confirm our hypothesis. The in vivo experimental results demonstrated that the expression of nuclear FOXO3 increased in the apoptotic neurons of the cerebral cortexes of rhesus macaques infected with simian human immunodeficiency virus (SHIV). The in vitro investigation showed that HIV-1 Tat activated FOXO3, causing it to move from the cytoplasm to the nucleus via the c-Jun N-terminal kinase (JNK) signaling pathway in SH-SY5Y cells. Moreover, FOXO3 down-regulated expression of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) and up-regulated the expression of the pro-apoptosis gene Bcl-2-like 11 (Bim) after entering the nucleus, eventually causing cellular apoptosis. Finally, reduction of nuclear FOXO3 reversed cellular apoptosis. Our results suggest that HIV-1 Tat induces FOXO3 to translocate from the cytoplasm to the nucleus via the JNK signaling pathway, leading to neuronal apoptosis. Agents targeting FOXO3 may provide approaches for restoring neuronal function in HAND.

Highlights

Impairment of cognition induced by human immunodeficiency virus (HIV) is known as HIVassociated neurocognitive disorder (HAND) and is an important chronic central nervous system syndrome affecting HIV-infected individuals (Antinori et al, 2007)
We found that expression of Forkhead box O3 (FOXO3) in the neuronal nucleus was elevated in HAND and that this phenomenon was associated with neuronal apoptosis in rhesus macaques infected with simian human immunodeficiency virus (SHIV), which were used as HAND animal models
There have been reports that FOXO3 is associated with cellular apoptosis and that its active form may facilitate apoptosis of macrophages infected by HIV-1 (Calnan and Brunet, 2008; Cui et al, 2008)

Summary

Introduction

Impairment of cognition induced by human immunodeficiency virus (HIV) is known as HIVassociated neurocognitive disorder (HAND) and is an important chronic central nervous system syndrome affecting HIV-infected individuals (Antinori et al, 2007). Patients with HAND may suffer from cognitive dysfunction, deficits in memory and attention, and impairment of motor skills, and so on (Antinori et al, 2007). SHIVSF162P4 is a chimeric simian human immunodeficiency virus, whose pathogenic features have been described (Polacino et al, 2008). This virus contains main genes from HIV-1SF162 (R5, macrophage-tropic [MT]/non-syncytium-inducing [NSI]) such as tat, rev, enu, and vpu, and spliced with the molecular clone simian immunodeficiency virus SIVmac239 (Tan et al, 1999). SHIVSF162P4 can cause immunological suppression and eventually cause rhesus macaques to develop acquired immune deficiency syndrome (AIDS)

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