Role of molecular mimicry to HIV-1 peptides in HIV-1 related immunologic thrombocytopenia

New York University School of Medicine, 550 First Ave, New York, NY 10016, USA.
Blood (Impact Factor: 10.45). 08/2005; 106(2):572-6. DOI: 10.1182/blood-2005-01-0243
Source: PubMed


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.

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    • "pylori) [140], human immunodeficiency virus (HIV) [111, 141, 142], hepatitis virus [143, 144], Epstein-Barr virus [145], cytomegalovirus [146], rubella virus [147], and the recently discovered novel Bunyavirus [148], have been linked with secondary ITP. Thrombocytopenia in these infections has been mainly attributed to antigenic mimicry, whereby antibodies targeting the micropathogens cross-react with platelet glycoproteins resulting in accelerated platelet clearance [111, 149]. "
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    ABSTRACT: Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1β, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-β and thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions.
    Advances in Hematology 09/2012; 2012(1):384685. DOI:10.1155/2012/384685
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    • "Later on, this IgG was found to be directed against GPIIIa 49-66 (Nardi et al. 1997). More recently, molecular mimicry was proposed between nef HIV-1 protein and GPIIIa 49-66 (Li et al. 2005) . Other chronic infectious diseases known to cause thrombocytopenia include chronic viral hepatitis, where CIC (Samuel et al. 1999) and PAIgG (Doi et al. 2002) are also implicated. "
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    ABSTRACT: Despite not being a criterion for severe malaria, thrombocytopenia is one of the most common complications of both Plasmodium vivax and Plasmodium falciparum malaria. In a systematic review of the literature, platelet counts under 150,000/mm³ ranged from 24-94% in patients with acute malaria and this frequency was not different between the two major species that affected humans. Minor bleeding is mentioned in case reports of patients with P. vivax infection and may be explained by medullary compensation with the release of mega platelets in the peripheral circulation by megakaryocytes, thus maintaining a good primary haemostasis. The speculated mechanisms leading to thrombocytopenia are: coagulation disturbances, splenomegaly, bone marrow alterations, antibody-mediated platelet destruction, oxidative stress and the role of platelets as cofactors in triggering severe malaria. Data from experimental models are presented and, despite not being rare, there is no clear recommendation on the adequate management of this haematological complication. In most cases, a conservative approach is adopted and platelet counts usually revert to normal ranges a few days after efficacious antimalarial treatment. More studies are needed to specifically clarify if thrombocytopenia is the cause or consequence of the clinical disease spectrum.
    Memórias do Instituto Oswaldo Cruz 08/2011; 106 Suppl 1:52-63. DOI:10.1590/S0074-02762011000900007 · 1.59 Impact Factor
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    • "GP IIb/IIIa gp120 Bettaieb 1996[93] GP IIIa gp41 Wiwanitkit 2008[94] GP IIIa aa49-66 nef Li 2005[95] GP IIIa aa749-761 gp41 Dominguez 1998[96] Platelets (antigen unknown) p24 "
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    ABSTRACT: Thrombocytopenia is common in HIV and SIV infection, and is often associated with disease progression. HIV and SIV-associated thrombocytopenia arise through multiple mechanisms, including decreased platelet production, increased platelet destruction due to HIV-mimetic anti-platelet antibodies, and increased use of activated platelets. Activated platelets have the potential to contribute to the pathogenesis of HIV and SIV by interacting directly with inflammatory cells and endothelium and by releasing soluble immunomodulatory cytokines.
    Drug Discovery Today Disease Mechanisms 06/2011; 8(1-2):e25-e32. DOI:10.1016/j.ddmec.2011.10.001
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