Blood. 2005 Jul 15;106(2):572-6. Epub 2005 Mar 17.
Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia
Li Z, Nardi MA, Karpatkin S
New York University School of Medicine, 550 First Ave, New York, NY 10016, USA
Significance:
Patients with early HIV-1 infection develop an autoimmune thrombocytopenia directed against a platelet membrane GPIIIa49-66 epitope. The Ab titer is inversely-related to platelet counts in patients and induces thrombocytopenia in mice. Using a peptide-phage display library we demonstrate that the thrombocytopenia can be secondary to cross-reactivity of anti-HIV Ab against a variant region of the HIV-Nef gene with the platelet membrane epitope, GPIIIa49-66.
Abstract:
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.
PMID: 15774614