Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia.
Patients with early HIV-1 infection develop an autoimmune thrombocytopenia in which antibody is directed against an immunodominant epitope of the beta3 (glycoprotein IIIa [GPIIIa]) integrin, GPIIIa49-66. This antibody induces thrombocytopenia by a novel complement-independent mechanism in which platelets are fragmented by antibody-induced generation of H2O2 derived from the interaction of platelet nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and 12-lipoxygenase. To examine whether sharing of epitope between host and parasite may be responsible for this immunodominant epitope, we screened for antibody-reactive peptides capable of inhibiting platelet lysis and oxidation in vitro, using a filamentous phage display 7-mer peptide library. Fourteen of these phage-peptide clones were identified. Five shared close sequence similarity with GPIIIa49-66, as expected. Ten were molecular mimics with close sequence similarity to HIV-1 proteins nef, gag, env, and pol. Seven were synthesized as 10-mers from their known HIV-1 sequence and found to inhibit anti-GPIIIa49-66-induced platelet oxidation/fragmentation in vitro. Three rabbit antibodies raised against these peptides induced platelet oxidation/fragmentation in vitro and thrombocytopenia in vivo when passively transferred into mice. One of the peptides shared a known epitope region with HIV-1 protein nef and was derived from a variant region of the protein. These data provide strong support for molecular mimicry in HIV-1-immunologic thrombocytopenia within polymorphic regions of HIV-1 proteins. A known epitope of nef is particularly incriminated.
Li
Zongdong
Z
New York University School of Medicine, 550 First Ave, New York, NY 10016, USA.
Nardi
Michael A
MA
Karpatkin
Simon
S
D000595:Amino Acid Sequence; D000818:Animals; D000939:Epitopes / Q000737:chemistry / Q000235:genetics; D005260:Female; D015483:HIV Antibodies; D015488:HIV Antigens / Q000737:chemistry / Q000235:genetics; D015658:HIV Infections / Q000150:complications* / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019151:Peptide Library; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000209:etiology* / Q000276:immunology*; D011817:Rabbits; D012191:Retroviridae Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D000939:Epitopes; D015483:HIV Antibodies; D015488:HIV Antigens; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012191:Retroviridae Proteins; C106958:platelet glycoprotein (GP)IIIa 49-66