Role of lymphocyte tolerance mechanisms in constraining the production of neutralizing HIV-1 antibodies, The

Abstract

HIV-1 broadly neutralizing antibodies (bnAbs) recognize conserved regions of the Envelope trimer and are capable of neutralizing up to 98% of cross-clade HIV-1 strains in vitro. Multiple bnAbs, with different specificities for Envelope, have been reported to recognize autoantigens, such as membrane phospholipids, nuclear antigens, and human ubiquitin ligase 3. One such bnAb CH98, identified in an HIV-1 infected individual with systemic lupus erythematosus, was found to recognize both dsDNA and to neutralize HIV-1 across clades. In this thesis, I investigated if tolerance checkpoints inhibit neutralizing HIV-1 antibody production by analyzing the quantitative and qualitative antibody responses in B6.Sle123 and MRL/lpr lupus prone and B6 wild type mouse strains following immunization with Envelope. This thesis shows that a subset of aged, lupus prone mice neutralize multiple tier 2 HIV-1 strains, even though the Envelope-specific IgG antibody response is quantitatively similar to wild type mice. Importantly, experimental breaks in immunological tolerance in wild type mice using pristane, the predominant hydrocarbon found in mineral oil, also leads to the production of tier 2 HIV-1 neutralizing antibodies, which increase in breadth and potency following Env immunization. In both genetically-prone and experimentally-induced mouse models of lupus, increased serum levels of IgM anti-histone H2A autoantibodies and total serum IgM concentrations significantly correlated with tier 2 HIV-1 neutralization. The production of histone H2A- and Envelope-reactive IgM was elicited from lupus prone B cells by TLR4, TLR7, and TLR9 signaling in a cell intrinsic manner. Both wild type and lupus prone B cells produce these cross-reactive IgM antibodies following co-culture with activated lupus prone, but not wild type, CD4+ T cells. My thesis reveals that lymphocyte peripheral tolerance checkpoints limiting innate and T cell help co-stimulation constrain neutralizing antibody responses against HIV-1 in wild type mice.