The tumor suppressor protein PML controls apoptosis induced by the HIV-1 envelope

Area of Science:

• Cell Biology
• Virology
• Cancer Biology

Background:

• Promyelomonocytic leukemia (PML) is a tumor suppressor implicated in various cancers.
• Human immunodeficiency virus-1 (HIV-1) envelope glycoprotein complex (Env) induces cell fusion, forming syncytia.
• The role of PML in HIV-1-induced syncytia and subsequent cell death is not fully understood.

Purpose of the Study:

• To investigate the role of PML aggregation in HIV-1-induced syncytia formation and apoptosis.
• To elucidate the molecular mechanisms by which PML influences syncytial cell death in HIV-1 infection.

Main Methods:

• In vitro studies using HIV-1 Env-expressing cells to induce syncytia and PML aggregation.
• Analysis of PML aggregation in patient samples (brain, lymph nodes, blood leukocytes) from HIV-1 infected individuals.
• Pharmacological inhibition of PML and assessment of its impact on ATM activation, DNA damage response, and apoptosis.
• Use of small interfering RNAs (siRNAs) to knockdown PML expression.

Main Results:

• PML aggregated in nuclear bodies within syncytia after nuclear fusion but before apoptosis.
• PML aggregation was observed in syncytia from HIV-1 infected patients and correlated with viral status.
• PML was essential for activating ATM phosphorylation within a complex involving topoisomerase IIbeta-binding protein 1.
• PML knockdown inhibited the ATM-dependent DNA damage response, p53 activation, and pro-apoptotic gene transcription, thereby suppressing syncytial apoptosis.

Conclusions:

• PML activation is an early, critical event in the apoptotic pathway of HIV-1-induced syncytia.
• PML plays a key role in orchestrating the DNA damage response leading to cell death in HIV-1 infection.
• Targeting PML may offer a therapeutic strategy to control HIV-1-induced cell death and pathogenesis.