Immunological tolerance as a barrier to protective HIV humoral immunity

•bnAbs isolated from HIV infected individuals display autoreactive specificities.•B cell development in HIV-1 bnAb Ig knockin mice is limited by central tolerance.•Autoimmune individuals and autoimmune-prone mouse strains produce HIV-1 bnAbs.•If a transient breach in tolerance would be helpful to develop bnAbs is not known.•How peripheral tolerance/B cell anergy limits the HIV response is not fully understood.

HIV-1 infection typically eludes antibody control by our immune system and is not yet prevented by a vaccine. While many viral features contribute to this immune evasion, broadly neutralizing antibodies (bnAbs) against HIV-1 are often autoreactive and it has been suggested that immunological tolerance may restrict a neutralizing antibody response. Indeed, recent Ig knockin mouse studies have shown that bnAb-expressing B cells are largely censored by central tolerance in the bone marrow. However, the contribution of peripheral tolerance in limiting the HIV antibody response by anergic and potentially protective B cells is poorly understood. Studies using mouse models to elucidate how anergic B cells are regulated and can be recruited into HIV-specific neutralizing antibody responses may provide insight into the development of a protective HIV-1 vaccine.

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