DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV

Area of Science:

• Immunology
• Cell Biology
• Virology

Background:

• Human immunodeficiency virus (HIV) infection of CD4(+) T cells induces caspase-independent cell death.
• This cell death pathway involves lysosomal membrane permeabilization (LMP) and mitochondrial outer membrane permeabilization (MOMP).

Purpose of the Study:

• To investigate the role of damage-regulated autophagy modulator (DRAM) in HIV-induced cell death.
• To elucidate the involvement of DRAM in host-pathogen interactions during HIV infection.

Main Methods:

• Utilized small interfering RNAs (siRNAs) to knock down DRAM, p53, Atg5, and Beclin gene expression.
• Assessed the impact of gene knockdown on autophagy, LMP, MOMP, cytochrome C release, and viral production.

Main Results:

• HIV infection induced p53-dependent DRAM expression.
• Knockdown of DRAM and p53 inhibited autophagy and LMP.
• DRAM knockdown suppressed cytochrome C release, MOMP, and cell death but increased viral infection and production.
• Inhibition of autophagy-related genes (Atg5, Beclin) had minimal effects on LMP and cell death.

Conclusions:

• DRAM plays a critical role in HIV-induced cell death, acting downstream of LMP.
• DRAM is involved in host-pathogen interactions, potentially serving as a defense mechanism by eliminating infected cells.
• The findings highlight DRAM as a novel target for HIV therapeutics, balancing viral control and host cell survival.