Identification Of A Conserved Self-Antigen Bearing The 2f5 Neutralizing Epitope Of The Hiv-1 Gp41 Membrane Proximal External Region

Accumulating evidence suggests that the efficient generation of neutralizing HIV-1 antibody may be proscribed by immunological tolerance. The majority of monoclonal human antibodies, including 2F5, that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian cells. Introduction and expression of the 2F5 VDJ rearrangement in knock-in mice results in a B-cell developmental blockade that is characteristic of immunological tolerance. If immunological tolerance does prevent regular expression of neutralizing 2F5-like antibody, then discrete autoantigens that structurally mimic the HIV-1 2F5 epitope are present in mammals. Here, we demonstrate that the 2F5 antibody precipitates a small number of proteins from mouse and human cells, including a major component with a molecular mass of about 50 kDa. We have identified this 50 kDa protein as kynureninase (KYNU), a conserved component of tryptophan metabolism. Remarkably, the conserved H3 domain of mammalian KYNU contains the core 2F5 epitope (ELDKWA), and mutation within this region greatly diminishes 2F5 binding. The 2F5 antibody and its inferred, unmutated precursor bind KYNU with high affinity and specificity. Indeed, recombinant human KYNU is an effective inhibitor of 2F5 binding to HIV-1 envelope. The nature of KYNU as autoantigen was previously unknown and our study suggests that mimicry of self-antigens may represent a general evolutionary strategy of viral pathogens.