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

Background: Anti-CD4 autoantibodies in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART) appear to prevent CD4+ T cell reconstitution, yet the mechanisms underlying their production remain unclear. Emerging evidence implicates Staphylococcus aureus and its peptidoglycan (PGN) in autoimmunity. Methods: Plasma from 32 ART-naive PWH, 53 ART-treated PWH, and 32 HIV-negative controls was analyzed for IgG autoantibodies and markers of S. aureus translocation. Causality was examined in EcoHIV-infected mice administered PGN from S. aureus or Bacillus subtilis. PGN structure was analyzed via mass spectrometry. Results: Among 87 autoantibodies, 40% were elevated in ART-naive PWH and largely normalized by ART; however, anti-CD4 IgGs remained elevated in PWH on ART. Anti-CD4 IgG levels inversely correlated with CD4+ T cell counts in ART-treated PWH and positively with S. aureus translocation. In mice, S. aureus PGN induced anti-CD4 IgGs, reduced gut CD4+ T cells, and promoted surface IgG binding and apoptosis in CD4+ T cells. Conclusion: S. aureus and its PGN translocation may contribute to anti-CD4 autoimmunity and hinder immune recovery in ART-treated PWH, representing a potential therapeutic target.