Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies.
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 because mice expressing the V(H) and V(L) regions of 2F5 have a block in B cell development that is 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. 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 an epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but they retain the SF3B3 4E10 epitope. 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 motifs shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.
Department of Immunology, Duke University, Durham, NC 27705, USA.
Guang
G
Yang
T Matt
TM
Holl
Yang
Y
Liu
Yi
Y
Li
Xiaozhi
X
Lu
Nathan I
NI
Nicely
Thomas B
TB
Kepler
S Munir
SM
Alam
Hua-Xin
HX
Liao
Derek W
DW
Cain
Leonard
L
Spicer
John L
JL
VandeBerg
Barton F
BF
Haynes
Garnett
G
Kelsoe
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D017124:Conserved Sequence; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006867:Hydrolases / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D057927:Hydrophobic and Hydrophilic Interactions; D007108:Immune Tolerance; D007114:Immunization; D051379:Mice; D009893:Opossums / Q000276:immunology; D010802:Phylogeny; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001324:Autoantigens; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C486349:SF3B3 protein, human; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1; D006867:Hydrolases; C021480:kynureninase