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Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies

ABSTRACT: Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance since mice expressing the VH and VL regions of 2F5 have a block in B-cell development characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. Here we identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes a conformational epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but retain all SF3B3 4E10 epitopes. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motif shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42673 | GEO | 2012/12/03

SECONDARY ACCESSION(S): PRJNA182712

REPOSITORIES: GEO

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Project description:Sanjuan2013 - Evolution of HIV T-cell epitope, control model Control model in which the virus targets a nonimmune cell type C (e.g., hepatocytes, epithelial cells, etc.), instead of T H cells. This model is described in the article: Immune activation promotes evolutionary conservation of T-cell epitopes in HIV-1. Sanjuán R, Nebot MR, Peris JB, Alcamí J. PLoS Biol. 2013 Apr;11(4):e1001523 Abstract: The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4(+) helper T lymphocytes (TH cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when TH cell infection is concomitant to epitope recognition (trans-infection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved TH epitopes may be counterproductive. This model is hosted on BioModels Database and identified by: MODEL1302180002 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Sanjuan2013 - Evolution of HIV T-cell epitope, immune activation model Model of cellular immune response against HIV. This model is described in the article: Immune activation promotes evolutionary conservation of T-cell epitopes in HIV-1. Sanjuán R, Nebot MR, Peris JB, Alcamí J. PLoS Biol. 2013 Apr;11(4):e1001523 Abstract: The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4(+) helper T lymphocytes (TH cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when TH cell infection is concomitant to epitope recognition (trans-infection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved TH epitopes may be counterproductive. Note from the author: this version of the model is more general that the one described in the paper. This is because: (i) it can consider simultaneously Th-epitope escape mutants, CTL-epitope escape mutants and full T-cell (Th and CTL) escape mutants, by setting the mutation rate of Th and CTL escape mutants to zero. (ii) It allows for back mutations, which were ignored in all the simulations shown in the paper. (iii) It allows for a fitness cost of escape mutants, which was set to zero in the article. (iv) pAPCs can be infected and produce viruses (the rate of viral production for pAPCs was set to zero in the paper). This model is hosted on BioModels Database and identified by: MODEL1302180001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies

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