Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction

Area of Science:

• Virology
• Cardiovascular Biology
• Immunology

Background:

• Cardiovascular diseases (CVD) are a leading cause of death in aging HIV-infected individuals on antiretroviral therapy (ART).
• The HIV protein Nef is produced even when viral replication is suppressed by ART.
• Endothelial activation and dysfunction are key contributors to CVD.

Purpose of the Study:

• To investigate if HIV-Nef protein can cause endothelial activation and dysfunction.
• To determine the mechanisms by which Nef affects endothelial cells.
• To assess the in vivo relevance of Nef-mediated endothelial effects.

Main Methods:

• Testing Nef protein transfer from HIV-infected cells to endothelial cells.
• Assessing Nef-induced endothelial cell apoptosis, reactive oxygen species (ROS) generation, and MCP-1 release.
• Utilizing CD4.Nef.GFP transgenic mice and chimeric SIV-infected macaques to study in vivo Nef transfer and presence.
• Analyzing Nef-induced signal transduction pathways (ROS, NF-kB).

Main Results:

• Nef protein transfers from HIV-infected or Nef-transfected cells to endothelial cells.
• Nef protein in endothelial cells is sufficient to induce apoptosis, ROS generation, and MCP-1 release.
• Nef-induced apoptosis is ROS-dependent, and MCP-1 production is NF-kB dependent.
• In vivo studies confirmed Nef transfer from T cells to endothelium and its presence in macaques.

Conclusions:

• HIV-Nef protein directly contributes to endothelial activation and dysfunction.
• Nef-mediated endothelial damage is a significant factor in CVD risk for HIV-infected individuals.
• Targeting Nef-associated pathways offers a potential therapeutic strategy for reducing CVD risk in this population.