Breaching peripheral tolerance promotes the production of HIV-1–neutralizing antibodies

Abstract

Schroeder et al. demonstrate that when peripheral tolerance is relaxed, tier 2 HIV-1–neutralizing antibodies can be elicited and identify new autoreactive antibody specificities against histone H2A capable of neutralizing tier 2 HIV-1.

Immunological tolerance as a barrier to protective HIV humoral immunity

“…The self antigens recognized by these HIV-1 bnAbs include the enzymes kynureninase and ubiquitin ligase E3A, SF3B3 splicing factor [19, 20], phospholipids (e.g. cardiolipin) [21], dsDNA [17] and, recently, histone H2A [22]. Why some bnAbs display autoreactivity remains speculative, although evidence exists for host mimicry by HIV-1 and as a possible mechanism used by the virus to avoid adaptive immunity [20].…”

“…As an extension of these observations, a recent study in our lab has demonstrated that autoimmune prone mice, with known defects in both central and peripheral tolerance, are able to produce neutralizing antibodies against tier 2 HIV-1 subtypes [22]. Interestingly, the lupus prone B6.Sle123 mouse strain, which harbors 3 chromosomal regions from the autoimmune NZM2410 strain on the C57BL/6 genetic background [59], produced tier 2 HIV-1 neutralizing antibodies following alum and TLR immunization alone, in the absence of Env ([22] and unpublished data).…”

“…Interestingly, the lupus prone B6.Sle123 mouse strain, which harbors 3 chromosomal regions from the autoimmune NZM2410 strain on the C57BL/6 genetic background [59], produced tier 2 HIV-1 neutralizing antibodies following alum and TLR immunization alone, in the absence of Env ([22] and unpublished data). Notably, we further demonstrated that an experimental breach of immunological tolerance in naïve wild type C57BL/6 mice using the pristane hydrocarbon [60] not only leads to the production of serum autoantibodies but also, upon immunization with HIV-1 gp140, leads to an Env-specific tier 2 HIV-1 neutralizing antibody response (Figure 1).…”

“…In this study, elevated serum titers of IgM autoantibodies against a lupus-associated autoantigen, histone H2A, correlated with tier 2 HIV-1 neutralization. Furthermore, IgM anti-H2A monoclonal antibodies isolated from immunized B6.Sle123 mice also demonstrated specificity for the CD4 binding site on gp120 and were able to neutralize tier 2 strains of HIV-1 [22]. Together, these findings highlight the ability of poly-/auto-reactive antibodies against SLE-associated autoantigens to neutralize HIV-1.…”

Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance

“…It has been speculated that some pathogens, including HIV, evade immune detection by exploiting “holes” in the B cell repertoire that are created by B cell tolerance mechanisms. Indeed, breaching peripheral B cell tolerance may actually facilitate generation of bNAbs [60]. The autoreactive VH4–34 BCR is expanded in the memory B cell compartment of malaria patients, and VH4–34-derived antibodies rise during acute malarial infection (though the extent of their protective capacity is unclear) [61].…”