Role of Molecular Mimickry of Hepatitis C Virus (HCV) Protein with Platelet GPIIIa in Hepatitis C-Related Immunologic Thrombocytopenia
Authors: Zhang Wei , Nardi Michael A. , Borkowsky William , Karpatkin Simon 
Published: April 2020

HIV-ITP patients have a unique Ab against platelet GPIIIa49-66 which induces oxidative platelet fragmentation in the absence of complement (Cell106: 551, 2001; JCI113: 973, 2004). Since HCV-ITP, like HIV-ITP, is associated with circulating immune complexes, we asked whether the complexes could contain platelet fragments induced by oxidative platelet fragmentation and whether HCV-ITP could be induced by molecular mimickry with an HCV peptide. The incidence of Hepatitis-C related ITP varies from 10–40% increasing with severity of liver disease. HIV-ITP is more frequent in drug abusers compared to non-drug abusers (37% vs 16%); and more severe in HIV-drug abusers than non-drug abusers (platelets &lt;10,000/ul in 52% vs 9%). A striking feature of HIV-infection in drug abusers is the frequent co-infection with HCV. HCV infection in non-drug abusers (~30%) increase to 90% in drug abusers. We asked whether coinfection with HCV facilitates ITP, and if so, which would be the mechanism. We screened a 7 mer peptide phage library with anti-GPIIIa49-66 Ab as bait for peptides showing homology sequences with HCV protein. Three clones had 70% homology with HCV protein, as well as a non-conserved core envelope 1 peptide, PHC09 (SAIHIRNASG). Three additional non-conserved envelope 1 peptides with 70% homology for PHC09 were found in the NIH data base (PHC09-H4, PHC09-H5 and PHC09-H6). The envelope 1 protein is a known neutralizing HCV epitope reactive with human MoAb vs 12 different HCV Envelope 1 isolates, containing the candidate linear epitope _ _ RN_SG_Y_. Sera from dually infected thrombocytopenic patients with HCV and HIV-ITP reacted strongly with PHC09 and correlated inversely with platelet count r2=0.7, p&lt;0.01, n=15. Ab raised against this peptide in GPIIIa −/− mice induced severe thrombocytopenia in wild-type mice, n=4. Affinity-purified IgG against PHC09 induced oxidative platelet fragmentation in vitro, n=5. Drug abusers dually infected with HCV and HIV had a greater incidence and severity of thrombocytopenia (&lt;30,000/ul) in 8/15 dually infected patients compared to 2/15 HCV-ITP (p&lt;0.025) or 3/15 HIV-ITP patients (p=0.06). This was associated with a greater incidence and titer of anti-GPIIIa49-66 Ab in 12/15 HCV-HIV-ITP compared to 2/15 HCV-ITP (P=0.001) or 6/15 HIV-ITP patients (p&lt;0.05). They also had a greater incidence of anti PHC09 Ab in 10/15 HCV-HIV-ITP patients compared to 3/15 HCV-ITP (p=0.004) or 1/15 HIV-ITP patients (p=0.001). Similar findings were obtained with PHC09-H5. NZB/W F1 mice injected with recombinant core envelope 1 developed Ab titers vs PHC09 and significantly lowered their platelet count by 60%, compared to controls, P&lt;0.001. Anti-PHC09 Ab correlated inversely with platelet count, r2=0.63, n=15, P&lt;0.05, n=8. Thus, 1) HCV-ITP complexes contain anti-PHC09 Ab capable of inducing oxidative platelet fragmentation; 2) HCV-ITP can be induced by molecular mimickry with HCV core envelope 1 protein, PHC09; 3) Dually infected ITP drug abusers with HIV and HCV have greater titers of anti-GPIIIa49-66/PHC09 Ab than HCV-ITP or HIV-ITP patients and more severe thrombocytopenia.