In 2017, our group first demonstrated that autoimmunity contributes to HIV pathogenesis, even without autoimmune disease. This concept is now broadly recognized, exemplified by the role of autoimmunity in severe COVID-19. In people with HIV (PWH) on suppressive antiretroviral therapy (ART), anti-CD4 autoantibodies may impair CD4+ T-cell recovery, though the mechanisms driving their production remain unclear. Building on evidence from our group and others that Staphylococcus aureus and its peptidoglycan (PGN) promote autoimmunity, we investigated their contribution to anti-CD4 IgG in HIV. 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 using protein array and ELISA. EcoHIV mice were injected intraperitoneally with saline, S. aureus PGN, or Bacillus subtilis PGN. PGN structures were compared by mass spectrometry. 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 markers of S. aureus translocation. In mice, S. aureus PGN induced anti-CD4 IgGs, reduced frequency of CD4+ T cells among total gut T cells, and promoted surface IgG binding and apoptosis in CD4+ T cells. S. aureus and its PGN translocation may drive anti-CD4 autoimmunity and hinder immune recovery in PWH on suppressive ART, highlighting S. aureus colonization as a therapeutic target and supporting the development of competitive probiotic interventions.IMPORTANCECurrently, no treatment is available for improving CD4+ T-cell recovery in people with HIV (PWH) on suppressive antiretroviral therapy (ART). Up to 20% of PWH on ART fail to restore peripheral CD4+ T-cell counts to levels observed in healthy individuals, a condition associated with increased morbidity and mortality and representing a major unmet challenge in HIV clinical care. Our study demonstrates that systemic Staphylococcus aureus translocation contributes to autoimmunity and impaired immune reconstitution in a subset of PWH on suppressive ART. These findings identify a previously unrecognized mechanism of immune failure and support a novel therapeutic strategy combining probiotics with ART to enhance immune recovery and reduce HIV-associated morbidity and mortality.
Cheng et al. (Fri,) studied this question.