The Mechanism Of HIV-1 Tat Activates FOXO3 To Induce Neuronal Apoptosis In HAND

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 and its main role is to participate in the regulation of HIV reverse transcription process,may be involved in the cellular apoptosis of HAND according to some reports.Forkhead box O3(FOXO3)is a multispecific transcription factor that has roles in many biological processes,including cellular apoptosis,but its role in HAND is still unclear.We employed tissue staining and related molecular biological experimental methods at the level of simian human immunodeficiency virus(SHIV)-infected rhesus macaques and in vitro cytology experiments,to confirm whether FOXO3 is activated by HIV-1 Tat and to investigate its role in neuronal apoptosis in HAND.The in vivo experimental results demonstrated that the expression of nuclear FOXOincreased in the apoptotic neurons of the cerebral cortexes of rhesus macaques infected with SHIV,and satellitosis and neuronophagia were also appeared in this region.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 treatment neuronal injury in HAND.