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

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.

New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System

“…A similar effect occurs with the viral protein Nef, which prevents autophagic maturation contributing to neurodegeneration [100]. In addition, Tat can induce neuronal apoptosis by activating forkhead box O3 (FOXO3), which is translocated to the nucleus through c-Jun N-terminal kinase (JNK) signaling to upregulate the expression of pro-apoptotic genes such as Bcl-2-like 11 (Bim) and downregulate anti-apoptotic factors such as B-cell lymphoma 2 (Bcl-2) [101].…”

Potential role of FoxO3a in the regulation of trophoblast development and pregnancy complications

“…These results may be attributed to the genes downstream of FoxO3a and related to apoptosis, including Bim, Fasl, TRAIL and Bcl. [38][39][40][41][42] In conclusion, our results found that FoxO3a plays an important role in the apoptosis, migration and invasion of HTR8-S/Vneo cells, which may be partially explained by its affinity to the ICAM1 promotor.…”

HIV-Associated Neurotoxicity: The Interplay of Host and Viral Proteins

“…Replication of HIV and the release of viral proteins damage the functioning of neurons leading to their death. In particular, studies have reported about HIV Nef and Tat proteins wherein HIV viral protein Nef prevents autophagic maturation leading to neurodegeneration [ 84 ] while Tat protein activates forkhead box O3 (FOXO3) leading to induction of neuronal apoptosis [ 85 ]. Furthermore, it is reported by Kaul et al that HIV-1, as well as its structural proteins mainly envelope protein, interferes directly affecting biological functions of neural stem and progenitor cells via the receptor-ligand axis between CXCR4-SDF-1 causing neuronal injury followed by the death of existing neurons leading to the development of HAD.…”