Kynureninase is the conserved self-antigen mimicked by the 2F5 Neutralizing Epitope of HIV-1 gp41 (105.35)

Abstract

Abstract Accumulating evidence suggests that the generation of neutralizing HIV-1 antibody may be proscribed by immunological tolerance. A significant majority of monoclonal human antibodies, including 2F5, that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to unknown components of mammalian cells. Knock-in mice expressing the VH and VL regions of 2F5 are characterized by a central defect in B-cell development that indicates the presence of a tolerizing autoantigen(s) that is mimicked by the membrane-proximal, 2F5 epitope of HIV-1 gp41. If immunological tolerance does indeed prevent regular expression of 2F5-like neutralizing HIV-1 antibody, then discrete autoantigens that structurally mimic the HIV-1 2F5 epitope must be present in those mammalian species unable to make 2F5-like antibody. We now demonstrate that the 2F5 antibody and its unmutated ancestor avidly bind human kynureninase (KYNU), a conserved enzyme of tryptophan metabolism. The H4 domain of most mammalian KYNU contains the complete 2F5 epitope (ELDKWA) of gp41; a H4 mutation of human KYNU to that (ELEKWA) of laboratory opossums resulted in a fully active enzyme completely unreactive with the 2F5 antibody. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of ELDKWA antibody but little or no response to adjacent gp41 epitopes. Identification of an epitope shared by most mammals and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.