The HIV-1 Vpr R77Q mutant alters host apoptotic gene regulation in CD4+ T cells

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• HIV-1 viral protein R (Vpr) is crucial for viral pathogenesis.
• The Vpr R77Q polymorphism is linked to reduced cell death and a non-inflammatory apoptotic phenotype in CD4+ T cells of long-term non-progressors (LTNPs).
• The underlying host mechanisms for the Vpr R77Q phenotype are not well understood.

Purpose of the Study:

• To investigate the host cellular responses to HIV-1 Vpr R77Q mutant infection.
• To elucidate the mechanisms by which Vpr R77Q influences cell death pathways and mitochondrial function.

Main Methods:

• RNA sequencing of HUT78 CD4+ T cells infected with wild-type (WT) or R77Q HIV-1.
• Differential gene expression analysis and functional enrichment.
• Assessment of mitochondrial membrane potential, BCL-2 protein levels, and modulation of BCL-2 function.

Main Results:

• At 72 hours post-infection, 289 genes were differentially expressed between WT and R77Q infections.
• WT infection upregulated anti-apoptotic BCL-2, while R77Q failed to activate these pathways.
• R77Q infection caused mitochondrial depolarization and reduced BCL-2 expression, indicating activation of intrinsic apoptosis.

Conclusions:

• HIV-1 Vpr R77Q reprograms host apoptotic signaling by impairing BCL-2-mediated survival and promoting mitochondrial dysfunction.
• This shift towards pro-apoptotic signaling provides a potential mechanism linking Vpr polymorphism to the LTNP phenotype.