Systemic Translocation of S. aureus Drives Anti-CD4 Autoimmunity in Treated HIV Infection

Area of Science:

• Immunology
• Microbiology
• Virology

Background:

• Anti-CD4 autoantibodies impede CD4+ T cell recovery in people with HIV (PWH) on antiretroviral therapy (ART).
• The mechanisms driving anti-CD4 autoantibody production in PWH are not fully understood.
• Emerging research suggests a link between Staphylococcus aureus, its peptidoglycan (PGN), and the development of autoimmunity.

Purpose of the Study:

• To investigate the role of Staphylococcus aureus peptidoglycan (PGN) in the development of anti-CD4 autoantibodies in people with HIV (PWH).
• To determine the association between S. aureus translocation, anti-CD4 autoantibodies, and CD4+ T cell counts in PWH on ART.
• To explore the causal relationship between S. aureus PGN and anti-CD4 autoimmunity in a mouse model.

Main Methods:

• Plasma samples from ART-naive PWH, ART-treated PWH, and HIV-negative controls were analyzed for IgG autoantibodies and S. aureus translocation markers.
• EcoHIV-infected mice were administered S. aureus or Bacillus subtilis PGN to assess causality.
• Peptidoglycan structure was characterized using mass spectrometry.

Main Results:

• Anti-CD4 IgG remained elevated in PWH on ART, inversely correlating with CD4+ T cell counts and positively with S. aureus translocation.
• S. aureus PGN administration in mice induced anti-CD4 IgGs, decreased gut CD4+ T cells, and promoted CD4+ T cell apoptosis.
• While many autoantibodies normalized with ART, anti-CD4 IgGs persisted in treated PWH.

Conclusions:

• Staphylococcus aureus translocation and its peptidoglycan may drive anti-CD4 autoimmunity in PWH on ART.
• This autoimmunity could hinder immune reconstitution and CD4+ T cell recovery.
• Targeting S. aureus and its PGN represents a potential therapeutic strategy for improving immune function in PWH.