Anti-nuclear antibodies in autoimmune prone mice are protective against HIV

Abstract

Abstract HIV broadly neutralizing antibodies (bnAbs) recognize conserved regions of the HIV envelope trimer, are capable of neutralizing up to 90% of cross-clade HIV strains in vitro, and have auto- and poly-reactive specificities. Multiple bnAbs, with different specificities for HIV envelope, have been reported to recognize autoantigens, such as membrane phospholipids, histones, and human ubiquitin ligase 3. Further, bnAb CH98 has been identified in an HIV infected individual with systemic lupus erythematosus (SLE) and was found to recognize both dsDNA and the CD4 binding site, as well as neutralize HIV strains of multiple clades in vitro. From this data, our lab hypothesized that both central and peripheral B cell tolerance checkpoints inhibit potentially neutralizing HIV-Ab responses, and that autoimmune prone individuals are capable of mounting neutralizing Ab responses. In order to further investigate this, we immunized age-matched, wild type and SLE prone strains of mice with HIV envelope proteins in adjuvant. We found that a subset of SLE prone mice neutralized multiple heterologous HIV strains 14 days post immunization, which was not observed in wild type mice. This neutralizing Ab response positively correlated with age and total serum IgM levels. SLE prone mice produced envelope-specific IgG of similar magnitude and isotypes as wild type mice, following envelope immunization. Using an array with 92 autoantigens, we found that the subset of SLE prone mice, which neutralize HIV, produce higher levels of histone H2A and dsDNA reactive IgM, as compared to the non-neutralizing SLE and wild type mice. Lastly, in vivo and in vitro studies show that activation of the autoimmune B cells by adjuvant is required for this neutralization activity.