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Blood, 15 July 2005, Vol. 106, No. 2, pp. 572-576.
Prepublished online as a Blood First Edition Paper on March 17, 2005; DOI 10.1182/blood-2005-01-0243.
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Submitted January 19, 2005
Accepted March 11, 2005
Role of molecular mimickry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia
Zongdong Li, Michael A Nardi, and Simon Karpatkin*
New York University School of Medicine, New York, NY, USA
* Corresponding author; email: simon.karpatkin{at}med.nyu.edu.
Patients with early HIV-1 infection develop an autoimmune thrombocytopenia in which Ab is directed against an immunodominant epitope of the  3 (GPIIIa) integrin, GPIIIa49-66. This Ab induces thrombocytopenia by a novel complement independent mechanism in which platelets are fragmented by Ab-induced generation of H2O2 derived from the interaction of platelet 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 Ab-reactive peptides capable of inhibiting platelet lysis and oxidation in vitro, utilizing 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. Nine were molecular mimicks 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 mutant region of the protein. These data provide strong support for molecular-mimickry in HIV-1-ITP within polymorphic regions of HIV-1 proteins. A known epitope of nef is particularly incriminated.
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